Benzoheterocyclic compounds and use thereof

ABSTRACT

Disclosed are compound of formula (I) and pharmaceutically accepted salts and prodrugs thereof, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1  and X 2  is as defined in the description. These compounds are protein kinases inhibitors, especially the inhibitors of Mek, which are useful in the treatment of cancers and inflammation of mammals. Disclosed are the treatment methods of cancers and inflammation of mammals as well as pharmaceutical compositions comprising the compounds described herein. The preparation of benzoheterocyclic compounds are disclosed. Disclosed are the preparation of potential drug candidates, such as benzooxazol, benzothiazol, benzothiadiazol and the like.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to People's Republic of China PatentApplication No. 201210014021.X filed Jan. 17, 2012, People's Republic ofChina Patent Application No. 201210189086.8 filed Jun. 8, 2012, People'sRepublic of China Patent Application No. 201210190520.4 filed Jun. 8,2012, and People's Republic of China Patent Application No.201210189087.2 filed Jun. 8, 2012, the disclosures of each of which arehereby incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to benzoheterocyclic compounds such asbenzothiadiazole, benzoxazole and benzothiazole derivatives, which areinhibitors of protein kinases such as MEK. The compounds may be usefulin the treatment of conditions or disorders where the MEK cascade isimplicated such as cancer and inflammatory diseases.

BACKGROUND OF THE INVENTION

Cell signaling through growth factor receptors and protein kinases is animportant regulator of cell growth, proliferation and differentiation.In normal cell growth, factors (i.e. PDGF or EGF and others), throughreceptor activation (i.e. ErbB2, EGFR, PDGFR), activate MAP(Mitogen-activating protein) kinase pathways. One of the most importantand most well understood MAP kinase pathways involved in normal anduncontrolled cell growth is the Ras/Raf/Mek/Erk kinase pathway. Inproliferative diseases, genetic mutations and/or overexpression of thegrowth factor receptors, downstream signaling proteins, or proteinkinases involved in the kinase pathway lead to uncontrolled cellproliferation and, eventually, tumor formation. For example, somecancers contain mutations which results in the activation of thispathway due to continuous production of growth factors. The statisticsshow that mutated, oncogenic forms of Ras are found in 50% of colonand >90% pancreatic cancers. Recently, bRaf mutations have beenidentified in more than 60% of malignant melanoma. Studies of primarytumor samples and cell lines have also shown constitutive oroveractivation of the Ras/Raf/Mek/Erk pathway in cancers of pancreas,colon, lung, ovary and kidney.

As constitutive or overactivation of MAP kinase cascade plays a pivotalrole in cell proliferation and differentiation, inhibition of thispathway is believed to be beneficial in hyperproliferative diseases. Mekis a key player in this pathway as it is downstream of Ras and Raf.Additionally, it is an attractive therapeutic target because the onlyknown substrates for Mek phosphorylation are the MAP kinases, Erk 1 and2. Hence, inhibition of MEK would block Ras/Raf/Mek/Erk pathway andresult in cell growth inhibition, especially the cell growth due to theoveractivation of Ras or Raf. Meanwhile Mek is also related toinflammatory disease and symptoms, including acute and chronicinflammation.

Inhibitors of Mek have shown some effects in clinical experiments ofnude mice. Recently, some Mek inhibitors have been applied at clinicalexperiments of people. Therefore, Mek is a potential new target and moreand more Mek inhibitors are developed and reported, for example, WO98/43960; WO 99/01421; WO 99/01426; WO 00/41505; WO 00/42002; WO00/41003; WO 00/41994; WO 00/42022; WO 00/42029; WO 00/68201; WO01/68619; WO 02/06213; WO 03/077914; WO 03/077855; WO 03/077914; WO05/023251; WO 05/023759; WO 05/051300; WO 05/051301; WO 05/051302; WO05/051906; WO 05/000818; WO 05/007616; WO 05/009975; WO 05/046665; WO06/134469; WO 07/044,084; WO 07/014,011; WO 07/121,269; WO 07/121,481;WO 07/071,951; WO 07/044,515; WO 08/021,389; WO 08/076,415; WO08/089,459; WO 08/078,086; WO 08/120,004; WO 08/124,085; WO 08/125,820;WO 09/018,238; WO 09/074,827; WO 09/013,426; WO 09/093,008; WO09/093,009; WO 09/093,013; WO 09/153,554 and so on.

However, many known MEK inhibitors suffer from weak inhibitory activity,intolerable toxicity or lack of desirable pharmaceutical properties.Thus, there remains a need for potent inhibitors of MEK with appropriatepharmaceutical properties for clinical applications.

BRIEF SUMMARY OF THE INVENTION

In one aspect, provided is a compound of the formula (I):

or a salt, solvate or prodrug thereof, wherein:

X¹ is CR¹¹ or N;

X² is O, S or carbonyl;

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido,hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy,halo-substituted C₁-C₁₀ alkoxy, acyloxy, mercapto, C₁-C₁₀ alkylthio,halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d),—N(R^(c))R^(d), —C(O)OR^(b), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl or C₃-C₁₀ cycloalkyl;

R^(a) is C₁-C₁₀ alkyl or C₆-C₁₄ aryl;

each R^(b), R^(c) and R^(d) is independently hydrogen or C₁-C₁₀ alkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)R⁹ or —NHSO₂R¹⁰;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl orC₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

R⁹ is C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl or C₆-C₁₄ aryl;

R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl,C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; and

R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀cycloalkyl moiety may be unsubstituted or substituted with one or moregroups independently selected from the group consisting of hydroxy, oxo,halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto;

provided that if X¹ is CH, X² is O or S, R¹ is methyl or chloro, R² ishydrogen and R³ is iodo, then R⁶ is —NHSO₂R¹⁰ or —C(O)N(R⁸)OR⁷ where R⁷is C₁-C₁₀ alkyl substituted with at least one hydroxy group.

In some embodiments, provided is a compound of the formula (J):

or a salt, solvate or prodrug thereof, wherein X¹, X², R¹, R², R³, R⁴,R⁵, R⁷ and R⁸ are as defined for the formula (I).

In another aspect, provided is any one of the MEK inhibitor compoundsdescribed herein present in a substantially pure form.

Also provided are pharmaceutical compositions and/or formulationscomprising any one of the compounds described herein and a carrier(e.g., a pharmaceutically acceptable carrier). In some embodiments, theformulation is suitable for administration to an individual. In someembodiments, the formulation comprises an effective amount of any one ofthe compounds described herein and a carrier (e.g., a pharmaceuticallyacceptable carrier). In another aspect, provided are pharmaceuticalformulations comprising a MEK inhibitor compound described herein or aMEK inhibitor compound described herein in combination with apharmaceutically acceptable carrier.

In another aspect, provided are methods for the treatment and/orprevention of a disease, condition, or disorder where the MEK pathwaycascade is implicated, such as a disease, condition, or disordermediated by MEK, comprising administering to an individual in needthereof a therapeutically effective amount of a compound describedherein, such as a compound of the formula (I), (J), (K), (A-I) or anyvariations thereof. In some embodiments, the disease or condition iscancer, chronic inflammatory disease, a skin disease, diabetes, an eyedisease, vasculogenesis, angiogenesis or chronic pain. In someembodiments, the disease or condition is rheumatoid arthritis orinflammatory bowel disease. In some embodiments, the disease orcondition is a cancer such as colon cancer, colorectal cancer, lungcancer, pancreatic cancer, breast cancer, ovarian cancer, prostatecancer or skin cancer.

Also provided is use of compounds detailed herein, such as a compound ofthe formula (I), (J), (K), (A-I) or any variations thereof, in themanufacture of a medicament for the treatment or prevention of a diseaseor condition which can be ameliorated by inhibition of MEK in anindividual, such as a mammal (e.g., human), in need thereof.

Kits comprising a compound as described herein and instructions for useare also provided. In one aspect, provided are kits for the treatment orprevention in an individual of a disease or condition mediated by MEK,comprising any one of the compounds detailed herein or apharmaceutically acceptable salt, solvate, or prodrug thereof; andpackaging. In some embodiments, the kit comprises a formulation of anyone of the compounds described herein and packaging.

Further provided are methods and processes of making compounds describedherein, or a salt (including a pharmaceutically acceptable salt),solvate or prodrug thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the anti-tumor effect of Compounds 1, 3, 9, 11, 17 and 19in a mouse xenograft model of human colon HT-29 cells.

FIG. 2 shows the anti-tumor effect of Compounds 1, 3, 9, 11, 17 and 19in a COLO-205 xenograft model.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

The term “halo” or “halogen”, by itself or as part of anothersubstituent, refers to and includes fluoro, chloro, bromo and iodo.

The term “alkyl”, by itself or as part of another substituent, refers toand includes saturated linear (i.e. unbranched) or branched hydrocarbonradicals, having the number of carbon atoms designated (i.e., C₁-C₁₀means one to ten carbons). Particular alkyl groups are those having 1 to10 carbon atoms (a “C₁-C₁₀ alkyl”). More particular alkyl groups arethose having 1 to 6 carbon atoms (a “C₁-C₆ alkyl”), 1 to 4 carbon atoms(a “C₁-C₄ alkyl”), 1 to 3 carbon atoms (a “C₁-C₃ alkyl”) or 1 to 2carbon atoms (a “C₁-C₂ alkyl”). Examples of “C₁-C₁₀ alkyl” include, butare not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl and the like.

The term “alkenyl”, by itself or as part of another substituent, refersto and includes unsaturated linear (i.e. unbranched) or branchedhydrocarbon radicals containing at least one carbon-carbon double bond,having the number of carbon atoms designated (i.e., C₂-C₁₀ means two toten carbons). Particular alkenyl groups are those having 2 to 10 carbonatoms (a “C₂-C₁₀ alkenyl”). More particular alkenyl groups are thosehaving 2 to 8 carbon atoms (a “C₂-C₈ alkenyl”) or 2 to 6 carbon atoms (a“C₂-C₆ alkenyl”). Examples of “C₂-C₁₀ alkenyl” include, but are notlimited to, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl,but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl,1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl,1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl,hex-1-en-1-yl, hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl,hex-5-en-1-yl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl,3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl,1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl,2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl,3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl,1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl,1-ethyl-2-methyl-2-propenyl, and the like.

The term “alkynyl”, by itself or as part of another substituent, refersto and includes unsaturated linear (i.e. unbranched) or branchedhydrocarbon radicals containing at least one carbon-carbon triple bond,having the number of carbon atoms designated (i.e., C₂-C₁₀ means two toten carbons). Particular alkynyl groups are those having 2 to 10 carbonatoms (a “C₂-C₁₀ alkynyl”). More particular alkenyl groups are thosehaving 2 to 8 carbon atoms (a “C₂-C₈ alkynyl”) or 2 to 6 carbon atoms (a“C₂-C₆ alkynyl”). Examples of “C₂-C₁₀ alkynyl” include, but are notlimited to, ethynyl, 1-propynyl, 2-propynyl, but-1-yn-1-yl,but-2-yn-1-yl, but-3-yn-1-yl, 1-methyl-2-propynyl, pent-1-yn-1-yl,pent-2-yn-1-yl, pent-3-yn-1-yl, pent-4-yn-1-yl, 1-methyl-2-butynyl,1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl,1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, hex-1-yn-1-yl,hex-2-yn-1-yl, hex-3-yn-1-yl, hex-4-yn-1-yl, hex-5-yn-1-yl,1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl,3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl,1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl,1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl, andthe like.

The term “cycloalkyl”, by itself or as part of another substituent,refers to and includes saturated monocyclic hydrocarbon radicals, havingthe number of carbon atoms designated (i.e., C₃-C₁₀ means three to tencarbons). Particular cycloalkyl groups are those having 3 to 10 carbonatoms (a “C₃-C₁₀ cycloalkyl”). More particular cycloalkyl groups arethose having 3 to 8 carbon atoms (a “C₃-C₈ cycloalkyl”), 3 to 6 carbonatoms (a “C₃-C₆ cycloalkyl”) or 3 to 4 carbon atoms (a “C₃-C₄cycloalkyl”). Examples of “C₃-C₁₀ cycloalkyl” include, but are notlimited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.

The term “aryl”, by itself or as part of another substituent, refers toand includes monocyclic or polycyclic aromatic hydrocarbon radicals,having the number of annular carbon atoms designated (i.e., C₆-C₁₄ meanssix to fourteen carbons). Particular aryl groups are those having 6 to14 annular carbon atoms (a “C₆-C₁₄ aryl”). Examples of “C₆-C₁₄ aryl”include, but are not limited to, phenyl, naphthyl, anthracenyl, and thelike. In some embodiments, an aryl may contain a single ring (e.g.,phenyl). In some embodiments, an aryl may contain multiple rings (e.g.,biphenyl). In some embodiments, an aryl may contain multiple condensedrings where at least one of the condensed rings is aromatic (e.g.,1,2,3,4-tetrahydronaphthyl and naphthyl).

The term “C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl” as used herein refers to aC₁-C₁₀ alkyl moiety which is substituted with a C₃-C₁₀ cycloalkylmoiety. Examples of “C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl” include, but arenot limited to, cyclopropylmethyl and the like.

The term “C₆-C₁₄ aryl C₁-C₁₀ alkyl” as used herein refers to a C₁-C₁₀alkyl moiety which is substituted with a C₆-C₁₄ aryl moiety. Examples of“C₆-C₁₄ aryl C₁-C₁₀ alkyl” include, but are not limited to, benzyl,phenylethyl, and the like.

The term “heterocyclyl” or “heterocycle” as used herein refers tomonocyclic or bicyclic radicals which may be fully saturated, partiallysaturated, or fully unsaturated or aromatic, having the number ofannular carbon atoms designated (i.e., C₃-C₁₀ means three to ten annularcarbon atoms) and containing at least one or more of the same ordifferent heteroatoms selected from N, S or O, provided that at leastone annular carbon atom is present and two annular oxygen atoms, ifpresent, do not occupy directly neighboring positions. A “heterocyclyl”or “heterocycle” may be a 3 to 15-membered saturated or partiallyunsaturated ring containing 1 to 4 heteroatoms selected from O, S and N,where the ring may be monocyclic, bicyclic or tricyclic, contain atleast one annular carbon atom and 1 to 3 nitrogen atoms, and/or 1 oxygenor sulfur atom or 1 or 2 oxygen and/or sulfur atoms; provided that whenmore than one annular oxygen atoms are present, they do not occupydirectly neighboring positions. Examples of “heterocyclyl” or“heterocycle” include, but are not limited to, 2-oxiranyl, 2-aziridinyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl,3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolinyl,4-isoxazolinyl, 5-isoxazolinyl, 3-isothiazolinyl, 4-isothiazolinyl,5-isothiazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,2-oxazolinyl, 4-oxazolinyl, 5-oxazolinyl, 2-thiazolinyl, 4-thiazolinyl,5-thiazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,4-triazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl,1,3,4-triazol-2-yl, 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl,2,4-dihydrofuran-2-yl, 2,4-dihydrofuran-3-yl, 2,3-dihydrothiophen-2-yl,2,3-dihydrothiophen-3-yl, 2,4-dihydrothiophen-2-yl,2,4-dihydrothiophen-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl,3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl,4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl,4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl,4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl,4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl,4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl,4-isothiazolin-5-yl, 2,3-dihydropyrazolin-1-yl,2,3-dihydropyrazolin-2-yl, 2,3-dihydropyrazolin-3-yl,2,3-dihydropyrazolin-4-yl, 2,3-dihydropyrazolin-5-yl,3,4-dihydropyrazoline-1-yl, 3,4-dihydropyrazolin-3-yl,3,4-dihydropyrazolin-4-yl, 3,4-dihydropyrazolin-5-yl,4,5-dihydropyrazolin-1-yl, 4,5-dihydropyrazolin-3-yl,4,5-dihydropyrazolin-4-yl, 4,5-dihydropyrazolin-5-yl,2,3-dihydrooxazolin-2-yl, 2,3-dihydrooxazolin-3-yl,2,3-dihydrooxazolin-4-yl, 2,3-dihydrooxazolin-5-yl,3,4-dihydrooxazolin-2-yl, 3,4-dihydrooxazolin-3-yl,3,4-dihydrooxazolin-4-yl, 3,4-dihydrooxazolin-5-yl,4,5-dihydrooxazolin-2-yl, 4,5-dihydrooxazolin-3-yl,4,5-dihydrooxazolin-4-yl, piperidin-2-yl, piperidine-3-yl,piperidine-4-yl, 1,3-dioxane-5-yl, tetrahydropyran-2-yl,tetrahydropyran-4-yl, tetrahydrothiophen-2-yl, hexahydrodiazin-3-yl,hexahydrodiazin-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl,hexahydropyrimidin-5-yl, piperazin-2-yl, 1,3,5-triazinan-2-yl,1,2,4-triazinan-3-yl, and the like.

The term “heteroaryl” as used herein refers to aromatic heterocyclyl orheterocycle as defined herein. Examples of “heteroaryl” include, but arenot limited to, 2-furanyl, 3-furanyl, thiophen-2-yl, thiophen-3-yl,1H-pyrrol-2-yl, 1H-pyrrol-3-yl, isoxazol-3-yl, isoxazol-4-yl,isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, oxazol-2-yl,oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,1H-imidazol-2-yl, 1H-imidazol-4-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,4-triazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl,1,3,4-triazol-2-yl, 1H-pyrrol-1-yl, 1H-pyrazol-1-yl, 1,2,4-triazol-1-yl,imidazol-1-yl, 1,2,3-triazol-1-yl, 1,3,4-triazol-1-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, diazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4,5-tetrazin-3-yl, indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl,indol-5-yl, indol-6-yl, indol-7-yl, benzo[d]imidazol-1-yl,benzo[d]imidazol-2-yl, benzo[d]imidazol-4-yl, benzo[d]imidazol-5-yl,indazol-1-yl, indazol-2-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl,indazol-6-yl, indazol-7-yl, benzofuran-2-yl, benzofuran-3-yl,benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl,benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl,benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl,benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl,benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, benzo[d]oxazol-2-yl,benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl,benzo[d]oxazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl,quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl,isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl,isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, and the like.

The term “heterocyclyl C₁-C₁₀ alkyl” as used herein refers to a C₁-C₁₀alkyl moiety which is substituted with a heterocyclyl moiety. Examplesof “heterocyclyl C₁-C₁₀ alkyl” include, but are not limited to,tetrahydrofuranylmethyl and the like.

The term “heteroaryl C₁-C₁₀ alkyl” as used herein refers to a C₁-C₁₀alkyl moiety which is substituted with a heteroaryl moiety. Examples of“heteroaryl C₁-C₁₀ alkyl” include, but are not limited to,oxazolylmethyl, pyridylethyl, and the like.

The term “solvate” refers to an aggregate formed by a solute molecule(such a compound of the invention) or ion with one or more solventmolecules via intermolecular forces such as Coulomb force, Van der Waalsforce, charge-dipole interactions and hydrogen bonding. When the solventis water, the solvate is referred to as “hydrate.”

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a human. The inventionmay find use in both human medicine and in the veterinary context.

The term “administration” and variants thereof (e.g., “administering”)in reference to a compound of the invention means introducing thecompound or a prodrug of the compound into the system of the animal inneed of treatment.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The term “treatment” refers to the treatment of a mammal afflicted witha pathological condition and refers to an effect that alleviates thecondition, e.g., by killing the cancerous cells, but also to an effectthat results in the inhibition of the progress of the condition, andincludes a reduction in the rate of progress, a halt in the rate ofprogress, amelioration of the condition, and cure of the condition.

The term “prevention” includes providing prophylaxis with respect tooccurrence or recurrence of a disease in an individual. An individualmay be predisposed to, susceptible to the disease, or at risk ofdeveloping the disease, but has not yet been diagnosed with the disease.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject (e.g. human) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each carrier,excipient, etc. must also be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation.

Unless indicated otherwise, the term “pharmaceutically acceptable salt”as used herein, refers to salts which are suitable for use in contactwith the tissues of a subject (e.g., human) without excessive adverseeffect. In some embodiments, pharmaceutically acceptable salts includesalts of a compound of the invention having an acidic group (forexample, but not limited to, potassium salts, sodium salts, magnesiumsalts, calcium salt, and the like) or a basic group (for example, butnot limited to, sulfate, hydrochloride, phosphate, nitrate, carbonate,and the like).

Compounds

Compounds according to the invention are detailed herein, including inthe Brief Summary of the Invention and the appended claims. Theinvention embraces all compounds detailed herein, including anysynthetic intermediates and uses thereof. The invention includes the useof all of the compounds described herein, including any and allstereoisomers, including geometric isomers (cis/trans), salts andsolvates of the compounds described herein, as well as methods of makingsuch compounds.

In one aspect, provided is a compound of the formula (I):

or a salt, prodrug or solvate thereof, wherein:

X¹ is CR¹¹ or N;

X² is O, S or carbonyl;

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido,hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy,alkylthio, halo-substituted C₁-C₁₀)alkylthio, amino, carboxy, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy,halo-substituted C₁-C₁₀ alkoxy, acyloxy, mercapto, alkylthio,halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d),—N(R^(c))R^(d), —C(O)OR^(b), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl or C₃-C₁₀ cycloalkyl;

R^(a) is C₁-C₁₀ alkyl or C₆-C₁₄ aryl;

each R^(b), R^(c) and R^(d) is independently hydrogen or C₁-C₁₀ alkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)R⁹ or —NHSO₂R¹⁰;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl orC₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

R⁹ is C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl or C₆-C₁₄ aryl;

R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl,C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; and

R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀cycloalkyl moiety may be unsubstituted or substituted with one or moregroups independently selected from the group consisting of hydroxy, oxo,halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto.

In some embodiments, the compound is of the formula (I), or a salt,prodrug or solvate thereof, provided that if X¹ is CH, X² is O or S, R¹is methyl or chloro, R² is hydrogen and R³ is iodo, then R⁶ is —NHSO₂R¹⁰or —C(O)N(R⁸)OR⁷ where R⁷ is C₁-C₁₀ alkyl substituted with at least onehydroxy group.

In another aspect, provided is a compound is of the formula (I):

or a salt, prodrug or solvate thereof, wherein:

X¹ is CR¹¹ or N;

X² is O, S or carbonyl;

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido,hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy,alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy,halo-substituted C₁-C₁₀ alkoxy, acyloxy, mercapto, alkylthio,halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d),—N(R^(c))R^(d), —C(O)OR^(b), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl or C₃-C₁₀ cycloalkyl;

R^(a) is C₁-C₁₀ alkyl or C₆-C₁₄ aryl;

each R^(b), R^(c) and R^(d) is independently hydrogen or C₁-C₁₀ alkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)R⁹ or —NHSO₂R¹⁰;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl orC₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

R⁹ is C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl or C₆-C₁₄ aryl;

R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl,C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; and

R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl, halo, C₁-C₁₀ alkoxy orC₁-C₁₀ alkylthio;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀cycloalkyl moiety may be unsubstituted or substituted with one or moregroups independently selected from the group consisting of hydroxy, oxo,halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto;

provided that if X¹ is CH, X² is O or S, R¹ is methyl or chloro, R² ishydrogen and R³ is iodo, then R⁶ is —NHSO₂R¹⁰ or —C(O)N(R⁸)OR⁷ where R⁷is C₁-C₁₀ alkyl substituted with at least one hydroxy group.

In some embodiments, the compound is of the formula (I), or a salt,prodrug or solvate thereof, wherein X¹ is N or CR¹¹. In someembodiments, X¹ is N. In some embodiments, X¹ is CR¹¹ where R¹¹ ishydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl. In some of theseembodiments, R¹¹ is hydrogen. In some of these embodiments, R¹¹ isC₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl. Insome other embodiments, R¹¹ is halo, C₁-C₁₀ alkoxy or C₁-C₁₀ alkylthio.

In some embodiments, the compound is of the formula (I), or a salt,prodrug or solvate thereof, wherein X² is O, S or carbonyl. In someembodiments, X² is S. In some embodiments, X² is O. In some embodiments,X² is carbonyl.

It is intended and understood that each and every variations of X²described for the formula (I) may be combined with each and everyvariations of X¹ described for the formula (I) as if each and everycombinations are individually described. For example, in someembodiments, X¹ is N and X² is S. In some embodiments, X¹ is N and X² isO or carbonyl. In some embodiments, X¹ is CR¹¹ and X² is O or S. In onevariation, X¹ is CR¹¹ and X² is O. In another variation, X¹ is CR¹¹ andX² is S. In some embodiments, X¹ is CH and X² is O or S. In onevariation, X¹ is CH and X² is O. In another variation, X¹ is CH and X²is S.

In some embodiments, the compound is of the formula (I), or a salt,prodrug or solvate thereof, wherein R¹ is hydrogen, halo, nitro, azido,hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In someembodiments, R¹ is halo (e.g., fluoro or chloro). In some embodiments,R¹ is nitro, azido, hydroxy, amino or carboxy. In some embodiments, R¹is C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy C₁-C₁₀alkylthio or halo-substituted C₁-C₁₀ alkylthio. In some embodiments, R¹is unsubstituted or substituted C₁-C₁₀ alkyl, unsubstituted orsubstituted C₂-C₁₀ alkenyl, unsubstituted or substituted C₂-C₁₀ alkynylor unsubstituted or substituted C₃-C₁₀ cycloalkyl. In some embodiments,R¹ is unsubstituted C₁-C₁₀ alkyl (e.g., methyl).

In some embodiments, R¹ is hydrogen, halo or C₁-C₆ alkyl. In someembodiments, R¹ is hydrogen, halo or C₁-C₄ alkyl. In some embodiments,R¹ is hydrogen, fluoro, chloro, bromo or C₁-C₂ alkyl. In someembodiments, R¹ is hydrogen, fluoro, chloro or methyl.

In some embodiments, the compound is of the formula (I), or a salt,prodrug or solvate thereof, wherein R² is hydrogen, halo, nitro, azido,hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy,alkylthio, halo-substituted alkylthio, amino, carboxy, alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In some embodiments, R² ishydrogen. In some embodiments, R² is halo, nitro, azido, hydroxy, C₁-C₁₀alkoxy, halo-substituted alkoxy, acyloxy, alkylthio, halo-substitutedalkylthio, amino or carboxy. In some embodiments, R² is C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl.

In some embodiments, R² is hydrogen, halo or C₁-C₆ alkyl. In someembodiments, R² is hydrogen, halo or C₁-C₄ alkyl. In some embodiments,R² is hydrogen, fluoro, chloro, bromo or C₁-C₂ alkyl. In someembodiments, R² is hydrogen, fluoro, chloro or methyl.

In some embodiments, the compound is of the formula (I), or a salt,prodrug or solvate thereof, wherein R³ is hydrogen, halo, cyano, nitro,azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted alkoxy, acyloxy,mercapto, alkylthio, halo-substituted alkylthio, —SO₂R^(a),—SO₂N(R^(c))R^(d), —N(R^(c))R^(d), —C(O)OR^(b), C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In some embodiments, R³ ishalo or cyano. In some embodiments, R³ is halo (e.g., iodo or bromo). Insome embodiments, R³ is nitro, azido, hydroxy or mercapto, —SO₂R^(a),—SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b). In some of theseembodiments, R³ is —SO₂R^(a) where R^(a) is C₁-C₁₀ alkyl or C₆-C₁₄ aryl.In one variation, R^(a) is unsubstituted or substituted C₁-C₁₀ alkyl(e.g., methyl). In some of these embodiments, R³ is —SO₂N(R^(c))R^(d)where R^(c) and R^(d) are independently hydrogen or C₁-C₁₀ alkyl. In onevariation, R³ is —SO₂N(R^(c))R^(d) where each R^(c) and R^(d) isindependently unsubstituted or substituted C₁-C₁₀ alkyl. In some ofthese embodiments, R³ is —N(R^(c))R^(d) where R^(c) and R^(d) areindependently hydrogen or C₁-C₁₀ alkyl. In one variation, R³ is—N(R^(c))R^(d) where each R^(c) and R^(d) is independently hydrogen ormethyl. In one particular variation, R³ is NMe₂. In some of theseembodiments, R³ is —C(O)OR^(b) where R^(b) is hydrogen or C₁-C₁₀ alkyl.In one variation, R³ is —C(O)OR^(b) where R^(b) is hydrogen (i.e., R³ iscarboxy). In another variation, R³ is —C(O)OR^(b) where R^(b) isunsubstituted or substituted C₁-C₁₀ alkyl (e.g., methyl or ethyl). Insome embodiments, R³ is C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy(e.g., trifluoromethoxy), acyloxy, C₁-C₁₀ alkylthio (e.g., methylthio),or halo-substituted C₁-C₁₀ alkylthio. In some embodiments, R³ is C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In someembodiments, R³ is unsubstituted or substituted C₁-C₁₀ alkyl, such ashalo-substituted C₁-C₁₀ alkyl (e.g., trifluoromethyl).

In some embodiments, R³ is hydrogen, halo, C₁-C₆ alkoxy, C₁-C₆ alkyl,halo-substituted C₁-C₆ alkyl, C₁-C₆ alkylthio, halo-substituted C₁-C₆alkoxy or halo-substituted C₁-C₆ alkylthio. In some embodiments, R³ isfluoro, chloro, bromo, iodo, C₁-C₄ alkyl, halo-substituted C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo-substituted C₁-C₄ alkoxy orhalo-substituted C₁-C₄ alkylthio. In some embodiments, R³ is bromo,iodo, C₁-C₂ alkylthio, halo-substituted C₁-C₂ alkylthio, C₁-C₂ alkoxy,halo-substituted C₁-C₂ alkoxy, C₁-C₂ alkyl or halo-substituted C₁-C₂alkyl. In some embodiments, R³ is bromo, iodo, methyl, methoxy,methylthio, trifluoromethyl, trifluoromethoxy or trifluoromethylthio.

In some embodiments, the compound is of the formula (I), or a salt,prodrug or solvate thereof, wherein R⁴ is hydrogen, halo, nitro, azido,hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In someembodiments, R⁴ is hydrogen. In some embodiments, R⁴ is halo, nitro,azido, hydroxy, amino or carboxy. In some embodiments, R⁴ is C₁-C₁₀alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio orhalo-substituted C₁-C₁₀ alkylthio. In some embodiments, R⁴ is C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl.

In some embodiments, R⁴ is hydrogen, halo or C₁-C₆ alkyl. In someembodiments, R⁴ is hydrogen or C₁-C₄ alkyl. In some embodiments, R⁴ ishydrogen or C₁-C₂ alkyl. In some embodiments, R⁴ is hydrogen.

In some embodiments, the compound is of the formula (I), or a salt,prodrug or solvate thereof, wherein R⁵ is hydrogen, halo, nitro, azido,hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In someembodiments, R⁵ is hydrogen or halo or unsubstituted or substitutedC₁-C₁₀ alkyl. In some embodiments, R⁵ is hydrogen. In some embodiments,R⁵ is fluoro. In some embodiments, R⁵ is C₁-C₁₀ alkyl (e.g., methyl). Insome embodiments, R⁵ is halo, nitro, azido, hydroxy, amino or carboxy.In some embodiments, R⁵ is C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀alkoxy, acyloxy, C₁-C₁₀ alkylthio or halo-substituted C₁-C₁₀ alkylthio.In some embodiments, R⁵ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynylor C₃-C₁₀ cycloalkyl.

In some embodiments, R⁵ is hydrogen, halo or C₁-C₆ alkyl. In someembodiments, R⁵ is hydrogen, halo or C₁-C₄ alkyl. In some embodiments,R⁵ is hydrogen, fluoro, chloro, bromo or C₁-C₂ alkyl. In someembodiments, R⁵ is hydrogen, fluoro, chloro or methyl.

It is intended and understood that each and every variations of R¹, R²,R³, R⁴ or R⁵ described for the formula (I) may be combined with each andevery variations of another one or more of R¹, R², R³, R⁴ and R⁵ and/oreach and every variations of X¹ and X² described for the formula (I) asif each and every combinations are individually described. For example,in some embodiments, provided is a compound of the formula (I), or asalt, prodrug or solvate thereof, where X¹ is N, X² is S, R¹ is halo(e.g., fluoro or chloro), R² is hydrogen, R³ is halo (e.g., iodo orbromo), R⁴ is hydrogen and R⁵ is fluoro. In some of these embodiments,X¹ is N, X² is S, R¹ is fluoro, R² is hydrogen, R³ is iodo, R⁴ ishydrogen and R⁵ is fluoro. In some of these embodiments, X¹ is N, X² isS, R¹ is chloro, R² is hydrogen, R³ is bromo, R⁴ is hydrogen and R⁵ isfluoro. In some embodiments, X¹ is CR¹¹ where R¹¹ is hydrogen, X² is S,R¹ is halo (e.g., fluoro or chloro), R² is hydrogen, R³ is halo (e.g.,iodo or bromo), R⁴ is hydrogen and R⁵ is fluoro. In some of theseembodiments, X¹ is CH, X² is S, R¹ is fluoro, R² is hydrogen, R³ isiodo, R⁴ is hydrogen and R⁵ is fluoro. In some of these embodiments, X¹is CH, X² is S, R¹ is chloro, R² is hydrogen, R³ is bromo, R⁴ ishydrogen and R⁵ is fluoro. In some embodiments, X¹ is CR¹¹ where R¹¹ ishydrogen, X² is O, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen,R³ is halo (e.g., iodo or bromo), R⁴ is hydrogen and R⁵ is fluoro. Insome of these embodiments, X¹ is CH, X² is O, R¹ is fluoro, R² ishydrogen, R³ is iodo, R⁴ is hydrogen and R⁵ is fluoro. In some of theseembodiments, X¹ is CH, X² is O, R¹ is chloro, R² is hydrogen, R³ isbromo, R⁴ is hydrogen and R⁵ is fluoro.

In some embodiments, the compound is of the formula (I), or a salt,prodrug or solvate thereof, wherein R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸,—C(O)N(R⁸)OR⁷, —C(O)R⁹ or —NHSO₂R¹⁰. In some embodiments, R⁶ is—C(O)OR⁷. In some embodiments, R⁶ is —C(O)NR⁷R⁸. In some embodiments, R⁶is —C(O)N(R⁸)OR⁷ where each R⁷ and R⁸ is independently hydrogen, C₁-C₁oalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl. In some ofthese embodiments, R⁷ is hydrogen, unsubstituted or substituted C₁-C₁₀alkyl or unsubstituted or substituted C₃-C₁₀ cycloalkyl. In someembodiments, R⁷ is C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl (e.g.,cyclopropylmethyl). In some of these embodiments, R⁷ is substitutedC₁-C₁₀ alkyl, such as C₁-C₁₀ alkyl substituted with at least one hydroxygroup. In some of these embodiments, R⁷ is C₁-C₁₀ alkyl substituted withat least 1 to 3 hydroxy groups. In some of these embodiments, R⁷ isC₁-C₆ alkyl substituted with at least 1 to 3 hydroxy groups. In some ofthese embodiments, R⁷ is C₁-C₄ alkyl substituted with 1 or 2 hydroxygroups (e.g., 2-hydroxyethyl, 3-hydroxy-2-methylpropyl,2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl). In some of theseembodiments, R⁷ is selected from the group consisting of 2-hydroxyethyl,3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and1,3-dihydroxy-2-propyl. In some of these embodiments, R⁷ is selectedfrom the group consisting of 2-hydroxyethyl,(R)-3-hydroxy-2-methylpropyl, (S)-3-hydroxy-2-methylpropyl,(R)-2,3-dihydroxypropyl, (S)-2,3-dihydroxypropyl and1,3-dihydroxy-2-propyl. In some of these embodiments, R⁷ isunsubstituted or substituted C₂-C₁₀ alkenyl or unsubstituted orsubstituted C₂-C₁₀ alkynyl. In some of these embodiments, R⁷ ishydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀cycloalkyl. In some of these embodiments, R⁸ is hydrogen orunsubstituted or substituted C₁-C₁₀ alkyl. In some of these embodiments,R⁸ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl,C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl. Insome embodiments, R⁶ is —C(O)R⁹ where R⁹ is unsubstituted or substitutedC₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl. In someembodiments, R⁶ is —NHSO₂R¹⁰ where R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl orC₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl. In some of these embodiments, R¹⁰ isunsubstituted or substituted C₁-C₁₀ alkyl or optionally substitutedC₃-C₁₀ cycloalkyl. In some of these embodiments, R¹⁰ is C₁-C₁₀ alkyl orC₃-C₁₀ cycloalkyl (e.g., cyclopropyl). In some of these embodiments, R¹⁰is unsubstituted or substituted C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl, such asC₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl substituted with at least one hydroxygroup. In some of these embodiments, R¹⁰ is C₁-C₁₀ alkyl C₃-C₁₀cycloalkyl substituted with 1 or 2 hydroxy groups (e.g.,1-(2,3-dihydroxypropyl)cyclopropyl). In some of these embodiments, R¹⁰is (R)-1-(2,3-dihydroxypropyl)cyclopropyl) or(S)-1-(2,3-dihydroxypropyl)cyclopropyl). In some of these embodiments,R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl,C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl.

In some embodiments, R⁶ is —C(O)N(R⁸)OR⁷, —C(O)NR⁷R⁸ or —NHSO₂R¹⁶; eachR⁷ and R⁸ is independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkyl C₁-C₆ alkyl or C₁-C₆ alkyl C₃-C₆ cycloalkyl; and R¹⁶ isC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl C₁-C₆ alkyl or C₁-C₆alkyl C₃-C₆ cycloalkyl; where each of the C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkyl C₁-C₆ alkyl and C₁-C₆ alkyl C₃-C₆ cycloalkyl groups maybe unsubstituted or substituted with one or more groups selected fromthe group consisting of hydroxy and mercapto. In some embodiments, R⁶ is—C(O)N(R⁸)OR⁷, —C(O)NR⁷R⁸ or —NHSO₂R¹⁶; each R⁷ and R¹⁶ is independentlyC₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkyl C₁-C₄ alkyl or C₁-C₄alkyl C₃-C₄ cycloalkyl, where each of the C₁-C₄ alkyl, C₃-C₄ cycloalkyl,C₃-C₄ cycloalkyl C₁-C₄ alkyl or C₁-C₄ alkyl C₃-C₄ cycloalkyl groups maybe unsubstituted or substituted with 1 to 6 hydroxy groups; and R⁸ ishydrogen or C₁-C₄ alkyl. In some embodiments, R⁶ is —C(O)N(R⁸)OR⁷ or—NHSO₂R¹⁶; each R⁷ and R¹⁰ is independently C₁-C₃ alkyl, C₃-C₄cycloalkyl, C₃-C₄ cycloalkyl C₁-C₃ alkyl or C₁-C₃ alkyl C₃-C₄cycloalkyl, where each of the C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄cycloalkyl C₁-C₃ alkyl or C₁-C₃ alkyl C₃-C₄ cycloalkyl groups may beunsubstituted or substituted with 1 to 3 hydroxy groups; and R⁸ ishydrogen. In some embodiments, R⁶ is —C(O)NHOR⁷ or —NHSO₂R¹⁶ where eachR⁷ and R¹⁰ is independently selected from the group consisting of2-hydroxyethyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2-propyl,3-hydroxy-2-methylpropyl, cyclopropyl and1-(2,3-dihydroxypropyl)cyclopropyl.

It is intended and understood that each and every variations of R⁶described for the formula (I) may be combined with each and everyvariations of X¹, X², R¹, R², R³, R⁴ and/or R⁵ described for the formula(I) as if each and every combinations are individually described. Forexample, in some embodiments, provided is a compound of the formula (I),or a salt, prodrug or solvate thereof, where X¹ is N or CR¹¹ where R¹¹is H, X² is O or S, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen,R³ is halo (e.g., iodo or bromo), R⁴ is hydrogen, R⁵ is fluoro and R⁶ is—C(O)N(R⁸)OR⁷ where R⁷ is C₁-C₁₀ alkyl substituted with at least 1 to 3hydroxy groups and R⁸ is hydrogen. In some of these embodiments, X¹ isN, X² is S, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen, R³ ishalo (e.g., iodo or bromo), R⁴ is hydrogen, R⁵ is fluoro and R⁶ is—C(O)NHOR⁷ where R⁷ is C₁-C₄ alkyl substituted with 1 or 2 hydroxygroups (e.g., 2-hydroxyethyl, 3-hydroxy-2-methylpropyl,2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl). In some of theseembodiments, X¹ is N, X² is S, R¹ is fluoro, R² is hydrogen, R³ is iodo,R⁴ is hydrogen, R⁵ is fluoro and R⁶ is —C(O)NHOCH₂CH₂OH. In some ofthese embodiments, X¹ is N, X² is S, R¹ is chloro, R² is hydrogen, R³ isbromo, R⁴ is hydrogen, R⁵ is fluoro and R⁶ is —C(O)NHOCH₂CH₂OH. In someembodiments, X¹ is CR¹¹ where R¹¹ is hydrogen, X² is O or S, R¹ is halo(e.g., fluoro or chloro), R² is hydrogen, R³ is halo (e.g., iodo orbromo), R⁴ is hydrogen, R⁵ is fluoro and R⁶ is —C(O)NHOR⁷ where R⁷ isC₁-C₄ alkyl substituted with 1 or 2 hydroxy groups (e.g.,2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and1,3-dihydroxy-2-propyl). In some of these embodiments, X¹ is CH, X² isS, R¹ is fluoro, R² is hydrogen, R³ is iodo, R⁴ is hydrogen, R⁵ isfluoro, and R⁶ is —C(O)NHOCH₂CH₂OH. In some of these embodiments, X¹ isCH, X² is S, R¹ is chloro, R² is hydrogen, R³ is bromo, R⁴ is hydrogenand R⁵ is fluoro. In some of these embodiments, X¹ is CH, X² is O, R¹ isfluoro, R² is hydrogen, R³ is iodo, R⁴ is hydrogen, R⁵ is fluoro, and R⁶is —C(O)NHOCH₂CH₂OH. In some of these embodiments, X¹ is CH, X² is O, R¹is chloro, R² is hydrogen, R³ is bromo, R⁴ is hydrogen, R⁵ is fluoro,and R⁶ is —C(O)NHOCH₂CH₂OH.

Also provided is a compound of the formula (I-1):

or a salt, prodrug or solvate thereof, wherein:

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido,hydroxy, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy,alkylthio, halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H, amino,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy,halo-substituted C₁-C₁₀ alkoxy, mercapto, C₁-C₁₀ alkylthio,halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H, amino, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(O)(C₆-C₁₄ aryl), or —NHSO₂R⁷;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl orC₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀cycloalkyl moiety may be unsubstituted or substituted with one or moregroups independently selected from the group consisting of hydroxy, oxo,halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto.

In some embodiments, the compound of the formula (I-1) is a compound ofthe formula (I-1-a), (I-1-b), (I-1-c) or (I-1-d):

or a salt, prodrug or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶,R⁷ and R⁸ are as defined for the formula (I-1).

In some embodiments, the compound is of the formula (I-1), (I-1-a),(I-1-b), (I-1-c) or (I-1-d), or a salt, prodrug or solvate thereof,wherein R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸, where applicable, are as definedfor the formula (I) or any applicable variations thereof.

In some embodiments, the compound of the formula (I-1) is a compound ofthe formula (I-1-e):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵ and R⁶ are asdefined for the formula (I), (I-1), or any applicable variationsthereof. In some particular embodiments of the compound of the formula(I-1-e), or a salt, prodrug or solvate thereof, wherein R⁶ is selectedfrom the group consisting of:

and R¹, R³ and R⁵ are as described in Table 1.

TABLE 1 R¹ R³ R⁵ R¹ R³ R⁵ R¹ R³ R⁵ F Br F F Br Me F Br H F I F F I Me FI H F SMe F F SMe Me F SMe H F OCF₃ F F OCF₃ Me F OCF₃ H F CF₃ F F CF₃Me F CF₃ H Cl Br F Cl Br Me Cl Br H Cl I F Cl I Me Cl I H Cl SMe F ClSMe Me Cl SMe H Cl OCF₃ F Cl OCF₃ Me Cl OCF₃ H Cl CF₃ F Cl CF₃ Me Cl CF₃H Me Br F Me Br Me Me Br H Me I F Me I Me Me I H Me SMe F Me SMe Me MeSMe H Me OCF₃ F Me OCF₃ Me Me OCF₃ H Me CF₃ F Me CF₃ Me Me CF₃ H

Also provided is a compound of the formula (I-2):

or a salt, prodrug or solvate thereof, wherein:

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido,hydroxy, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy,C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H,amino, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy,halo-substituted C₁-C₁₀ alkoxy, mercapto, C₁-C₁₀ alkylthio,halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H, amino, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(O)(C₆-C₁₄ aryl), or —NHSO₂R⁷;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl orC₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀cycloalkyl moiety may be unsubstituted or substituted with one or moregroups independently selected from the group consisting of hydroxy, oxo,halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto.

In some embodiments, the compound is of the formula (I-2) wherein R¹,R², R³, R⁴, R⁵, R⁶ and R¹¹ are as defined for the formula (I-2) providedthat if R¹ is methyl or chloro, R² is hydrogen and R³ is iodo, then R⁶is —NHSO₂R⁷ where R⁷ is as defined for the formula (I-2), or—C(O)N(R⁸)OR⁷ where R⁷ is C₁-C₁₀ alkyl substituted with at least onehydroxy group.

In some embodiments, the compound of the formula (I-2) is a compound ofthe formula (I-2-a), (I-2-b), (I-2-c) or (I-2-d):

or a salt, prodrug or solvate thereof, wherein R², R³, R⁴, R⁵, R⁶, R⁷,R⁸ and R¹¹ are as defined for the formula (I-2).

In some embodiments, the compound is of the formula (I-2), (I-2-a),(I-2-b), (I-2-c) or

(I-2-d), or a salt, prodrug or solvate thereof, wherein R², R³, R⁴, R⁵,R⁶, R⁷, R⁸ and R¹¹, where applicable, are as defined for the formula (I)or any applicable variations thereof.

In some embodiments, the compound of the formula (I-2) is a compound ofthe formula (I-2-e):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵ and R⁶ are asdefined for the formula (I), (I-2), or any applicable variationsthereof. In some particular embodiments of the compound of the formula(I-2-e), or a salt, prodrug or solvate thereof, wherein R⁶ is selectedfrom the group consisting of:

and R¹, R³ and R⁵ are as specified in Table 2.

TABLE 2 R¹ R³ R⁵ R¹ R³ R⁵ R¹ R³ R⁵ F Br F F Br Me F Br H F I F F I Me FI H F SMe F F SMe Me F SMe H F OCF₃ F F OCF₃ Me F OCF₃ H F CF₃ F F CF₃Me F CF₃ H Cl Br F Cl Br Me Cl Br H Cl SMe F Cl I Me Cl I H Cl OCF₃ F ClSMe Me Cl SMe H Cl CF₃ F Cl OCF₃ Me Cl OCF₃ H Me Br F Cl CF₃ Me Cl CF₃ HMe SMe F Me Br Me Me Br H Me OCF₃ F Me I Me Me I H Me CF₃ F Me SMe Me MeSMe H Me OCF₃ H Me OCF₃ Me Me CF₃ H Me CF₃ Me

Also provided is a compound of the formula (I-3):

or a salt, prodrug or solvate thereof, wherein:

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido,hydroxy, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy,C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H,amino, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy,halo-substituted C₁-C₁₀ alkoxy, mercapto, C₁-C₁₀ alkylthio,halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H, amino, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(O)(C₆-C₁₄ aryl), or —NHSO₂R⁷;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl orC₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀cycloalkyl moiety may be unsubstituted or substituted with one or moregroups independently selected from the group consisting of hydroxy, oxo,halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto.

In some embodiments, the compound is of the formula (I-3) wherein R¹,R², R³, R⁴, R⁵, R⁶ and R¹¹ are as defined for the formula (I-3) providedthat if R¹ is methyl or chloro, R² is hydrogen and R³ is iodo, then R⁶is —NHSO₂R⁷ where R⁷ is as defined for the formula (I-3), or—C(O)N(R⁸)OR⁷ where R⁷ is C₁-C₁₀ alkyl substituted with at least onehydroxy group.

In some embodiments, the compound of the formula (I-3) is a compound ofthe formula (I-3-a), (I-3-b), (I-3-c) or (I-3-d):

or a salt, prodrug or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸ and R¹¹ are as defined for the formula (I-3).

In some embodiments, the compound is of the formula (I-3), (I-3-a),(I-3-b), (I-3-c) or (I-3-d), or a salt, prodrug or solvate thereof,wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹¹, where applicable, are asdefined for the formula (I) or any applicable variations thereof.

In some embodiments, the compound of the formula (I-3) is a compound ofthe formula (I-3-e):

or a salt, prodrug or solvate thereof, wherein R³, R⁵ and R⁶ are asdefined for the formula (I), (I-3), or any applicable variationsthereof. In some particular embodiments of the compound of the formula(I-3-e), or a salt, prodrug or solvate thereof, wherein R⁶ is selectedfrom the group consisting of:

and R¹, R³ and R⁵ are as specified in Table 2.

In one embodiment, provided is a compound of the formula (J):

or a salt, prodrug or solvate thereof, where X¹, X², R¹, R², R³, R⁴, R⁵,R⁷ and R⁸ are as described for the formula (I), or any variationsthereof. It is intended and understood that each and every variations ofX¹, X², R¹, R², R³, R⁴, R⁵, R⁷ and R⁸, and each and every combinationsthereof described herein for the formula (I) apply to the formula (J) asif each and every variations and combinations are individuallydescribed. For example, in some embodiments, provided is a compound ofthe formula (J), or a salt, prodrug or solvate thereof, where X¹ is N orCR¹¹ where R¹¹ is H, X² is O or S, R¹ is halo (e.g., fluoro or chloro),R² is hydrogen, R³ is halo (e.g., iodo or bromo), R⁴ is hydrogen, R⁵ isfluoro, R⁷ is C₁-C₁₀ alkyl substituted with at least 1 to 3 hydroxygroups and R⁸ is hydrogen.

In one embodiment, the compound of the formula (J) is of the formula(J-1):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵ and R⁷ are asdefined for the formula (J) or formula (I) or any variations thereof. Insome of these embodiments, R¹ is halo or unsubstituted or substitutedC₁-C₁-C₁₀ alkyl; R³ is halo, unsubstituted or substituted C₁-C₁-C₁₀alkyl, alkoxy, halo-substituted C₁-C₁₀ alkoxy, alkylthio,halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d),—N(R^(c))R^(d) or —C(O)OR^(b); R⁵ is hydrogen, halo or unsubstituted orsubstituted C₁-C₁₀ alkyl; and R⁷ is hydrogen, unsubstituted orsubstituted C₁-C₁₀ alkyl, unsubstituted or substituted C₃-C₁₀cycloalkyl, or unsubstituted or substituted C₃-C₁₀ cycloalkyl C₁-C₁₀alkyl.

In some embodiments, provided is a compound of the formula (J-1), or asalt, prodrug or solvate thereof, wherein R¹ is halo (e.g., fluoro orchloro) or C₁-C₁₀ alkyl (e.g., methyl). In some of these embodiments, R³is halo (e.g., iodo or bromo), substituted C₁-C₁₀ alkyl (e.g.,trifluoromethyl), halo-substituted C₁-C₁₀ alkoxy (e.g.,trifluoromethoxy), C₁-C₁₀ alkylthio (e.g., methylthio), —SO₂R^(a),—SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b). In some of theseembodiments, R³ is —SO₂R^(a) where R^(a) is unsubstituted or substitutedC₁-C₁₀ alkyl (e.g., SO₂Me). In some of these embodiments, R³ is—N(R^(c))R^(d) where R^(c) and R^(d) are independently hydrogen orC₁-C₁₀ alkyl (e.g., NMe₂). In some of these embodiments, R³ is—C(O)OR^(b) where R^(b) is unsubstituted or substituted C₁-C₁₀ alkyl(e.g., CO₂Me). In some of these embodiments, R⁵ is hydrogen, halo (e.g.,fluoro) or C₁-C₁₀ alkyl (e.g., methyl). In some of these embodiments, R⁷is C₁-C₁₀ alkyl substituted with at least one hydroxy group. In some ofthese embodiments, R⁷ is C₁-C₁₀ alkyl substituted with at least 1 to 3hydroxy groups. In some of these embodiments, R⁷ is C₁-C₆ alkylsubstituted with at least 1 to 3 hydroxy groups. In some of theseembodiments, R⁷ is C₁-C₄ alkyl substituted with 1 or 2 hydroxy groups(e.g., 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and1,3-dihydroxy-2-propyl). In some of these embodiments, R⁷ isunsubstituted or substituted C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl. In some ofthese embodiments, R⁷ is unsubstituted or substituted C₃-C₆ cycloalkylC₁-C₆ alkyl. In some of these embodiments, R⁷ is unsubstituted orsubstituted C₃-C₄ cycloalkyl C₁-C₃ alkyl (e.g., cyclopropylmethyl). Insome particular embodiments, the compound is of the formula (J-1), or asalt, prodrug or solvate thereof, wherein R¹ is fluoro or chloro, R³ isiodo or bromo, R⁵ is fluoro, and R⁷ is selected from the groupconsisting of cyclopropylmethyl, 2-hydroxyethyl,3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and1,3-dihydroxy-2-propyl. In some of these embodiments, R⁷ is selectedfrom the group consisting of 2-hydroxyethyl, 3-hydroxy-2-methylpropyl,2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl. In some of theseembodiments, R⁷ is selected from the group consisting of 2-hydroxyethyl,(R)-3-hydroxy-2-methylpropyl, (S)-3-hydroxy-2-methylpropyl,(R)-2,3-dihydroxypropyl, (S)-2,3-dihydroxypropyl and1,3-dihydroxy-2-propyl.

In one embodiment, the compound of the formula (J) is of the formula(J-2):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵, R⁷ and R¹¹are as defined for the formula (J), (I) or any variations thereof.

In one embodiment, the compound of the formula (J) is of the formula(J-3):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵, R⁷ and R¹¹are as defined for the formula (J), (I) or any variations thereof.

In some embodiments, provided is a compound of the formula (J-2) or(J-3), or a salt, prodrug or solvate thereof, wherein R¹ is halo orunsubstituted or substituted C₁-C₁₀ alkyl; R³ is halo, unsubstituted orsubstituted C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy,acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a),—SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b); R⁵ is hydrogen, haloor unsubstituted or substituted C₁-C₁₀ alkyl; R⁷ is C₁-C₁₀ alkylsubstituted with at least one hydroxy group; and R¹¹ is hydrogen.

In some embodiments, provided is a compound of the formula (J-2) or(J-3), or a salt, prodrug or solvate thereof, wherein R¹ is halo (e.g.,fluoro or chloro) or C₁-C₁₀ alkyl (e.g., methyl). In some of theseembodiments, R³ is halo (e.g., iodo or bromo), substituted C₁-C₁₀ alkyl(e.g., trifluoromethyl), halo-substituted C₁-C₁₀ alkoxy(e.g.,trifluoromethoxy), C₁-C₁₀ alkylthio(e.g., methylthio), —SO₂R^(a),—SO₂N(R^(c))R^(d), —N(R^(c))R^(d), or —C(O)OR^(b). In some of theseembodiments, R³ is —SO₂R^(a) where R^(a) is unsubstituted or substitutedC₁-C₁₀ alkyl (e.g., SO₂Me).

In some of these embodiments, R³ is —N(R^(c))R^(d) where R^(c) and R^(d)are independently hydrogen or C₁-C₁₀ alkyl (e.g., NMe₂). In some ofthese embodiments, R³ is —C(O)OR^(b) where R^(b) is unsubstituted orsubstituted C₁-C₁₀ alkyl (e.g., CO₂Me). In some of these embodiments, R⁵is hydrogen, halo (e.g., fluoro) or C₁-C₁₀ alkyl (e.g., methyl). In someof these embodiments, R⁷ is C₁-C₁₀ alkyl substituted with at least 1 to3 hydroxy groups. In some of these embodiments, R⁷ is C₁-C₆ alkylsubstituted with at least 1 to 3 hydroxy groups. In some of theseembodiments, R⁷ is C₁-C₄ alkyl substituted with 1 or 2 hydroxy groups(e.g., 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and1,3-dihydroxy-2-propyl). In some particular embodiments, the compound isof the formula (J-2) or (J-3), or a salt, prodrug or solvate thereof,wherein R¹ is fluoro or chloro, R³ is iodo or bromo, R⁵ is fluoro, andR⁷ is selected from the group consisting of 2-hydroxyethyl,3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and1,3-dihydroxy-2-propyl.

In one embodiment, the compound of the formula (J) is of the formula(J-4):

or a salt, prodrug or solvate thereof, wherein X¹, X², R¹ and R³ are asdefined for the formula (J) or (I), or any variations thereof. In onevariation, X¹ is N and X² is S. In another variation, X¹ is CH and X² isO. In yet another variation, X¹ is CH and X² is S. In some of thesevariations, R¹ is fluoro and R³ is iodo. In some of these variations, R¹is chloro and R³ is bromo.

In another embodiment, the compound is of the formula (K):

or a salt, prodrug or solvate thereof, where X¹, X², R¹, R², R³, R⁴, R⁵and R¹⁰ are as described for the formula (I), or any variations thereof.It is intended and understood that each and every variations of X¹, X²,R², R³, R⁴, R⁵ and R¹⁰ and each and every combinations thereof describedherein for the formula (I) apply to the formula (K) as if each and everyvariations and combinations are individually described. For example, insome embodiments, provided is a compound of the formula (K), or a salt,prodrug or solvate thereof, where X¹ is N or CR¹¹ where R¹¹ is H, X² isO or S, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen, R³ is halo(e.g., iodo or bromo), R⁴ is hydrogen, R⁵ is fluoro, and R¹⁰ is C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl. In onevariation, X¹ is N and X² is S. In another variation, X² is S and X¹ isCR¹¹ where R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl. In anothervariation, X² is O and X¹ is CR¹¹ where R¹¹ is hydrogen, C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkylC₁-C₁₀ alkyl.

In one embodiment, the compound of the formula (K) is of the formula(K-1):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵ and R¹⁰ are asdefined for the formula (K), (I) or any variations thereof.

In one embodiment, the compound of the formula (K) is of the formula(K-2):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵, R¹⁰ and R¹¹are as defined for the formula (K), (I) or any variations thereof.

In one embodiment, the compound of the formula (K) is of the formula(K-3):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵, R¹⁰ and R¹¹are as defined for the formula (K), (I) or any variations thereof.

In some embodiments, provided is a compound of the formula (K-1), (K-2)or (K-3), or a salt, prodrug or solvate thereof, wherein R¹ is halo orunsubstituted or substituted C₁-C₁₀ alkyl; R³ is halo, unsubstituted orsubstituted C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy,acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a),—SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b); R⁵ is hydrogen, haloor unsubstituted or substituted C₁-C₁₀ alkyl; R¹⁰ is unsubstituted orsubstituted C₁-C₁₀ alkyl, unsubstituted or substituted C₃-C₁₀ cycloalkylor unsubstituted or substituted C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; and R¹¹is hydrogen where present. In some of these embodiments, R¹ is halo(e.g., fluoro or chloro). In some of these embodiments, R³ is halo(e.g., iodo or bromo). In some of these embodiments, R³ is —SO₂R^(a)where R^(a) is unsubstituted or substituted C₁-C₁₀ alkyl (e.g., SO₂Me).In some of these embodiments, R³ is —N(R^(c))R^(d) where R^(c) and R^(d)are independently hydrogen or C₁-C₁₀ alkyl (e.g., NMe₂). In some ofthese embodiments, R³ is —C(O)OR^(b) where R^(b) is unsubstituted orsubstituted C₁-C₁₀ alkyl (e.g., CO₂Me). In some of these embodiments, R³is SO₂Me or CO₂Me. In some of these embodiments, R⁵ is hydrogen, halo(e.g., fluoro) or C₁-C₁₀ alkyl (e.g., methyl). In one particularembodiment, R⁵ is fluoro. In some of these embodiments, R¹⁰ is C₁-C₁₀alkyl, C₃-C₁₀ cycloalkyl, or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl substitutedwith at least one hydroxy group. In some of these embodiments, R¹⁰ isC₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl substituted with 1 or 2 hydroxy groups(e.g., 1-(2,3-dihydroxypropyl)cyclopropyl).

In some embodiments, provided is a compound of the formula (K-1), (K-2)or (K-3), or a salt, prodrug or solvate thereof, wherein R¹ is fluoro orchloro, R³ is iodo or bromo, R⁵ is fluoro, R¹⁰ is selected from thegroup consisting of cyclopropyl and 1-(2,3-dihydroxypropyl)cyclopropyl,and R¹¹ is hydrogen where present. In some of these embodiments, R¹ isfluoro R³ is iodo, R⁵ is fluoro, R¹⁰ is1-(2,3-dihydroxypropyl)cyclopropyl and R¹¹ is absent for a compound ofthe formula (K-1) or is hydrogen for a compound of the formula (K-2) or(K-3).

Representative examples of compounds detailed herein, includingintermediates and final compounds according to the invention aredepicted in the Tables and Examples herein. It is understood that in oneaspect, any of the compounds may be used in the methods detailed herein,including, where applicable, intermediate compounds that may be isolatedand administered to an individual.

Representative compounds of the invention are shown in Table 3. In someembodiments, the invention provides a compound of Table 3, in its freebase form or as pharmaceutically acceptable salts, or a stereoisomerthereof

TABLE 3 Exemplary compounds Compound No. Structure Compound Name 1

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6- carboxamide 2

N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole- 6-carboxamide 3

5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6- carboxamide 4

5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d]oxazole- 6-carboxamide 5

N-(4-fluoro-5-((2-fluoro-4- iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropanesulfonamide 6

N-(4-fluoro-5-((2-fluoro-4- iodophenyl)amino)benzo[d]oxazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1- sulfonamide 7

N-(5-((4-bromo-2-chlorophenyl)amino)-4- fluorobenzo[d]oxazol-6-yl)cyclopropanesulfonamide 8

N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide 9

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6- carboxamide 10

N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole- 6-carboxamide 11

5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]thiazole-6- carboxamide 12

5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d]thiazole- 6-carboxamide 13

N-(4-fluoro-5-((2-fluoro-4- iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropanesulfonamide 14

1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide 15

N-(5-((4-bromo-2-chlorophenyl)amino)-4- fluorobenzo[d]thiazol-6-yl)cyclopropanesulfonamide 16

N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide 17

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole- 6-carboxamide 18

N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2- fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole- 6-carboxamide 19

5-((4-bromo-2-chlorophenyl)amino)-4-fluoro- N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6- carboxamide 20

5-((4-bromo-2-chlorophenyl)amino)-N-(2,3- dihydroxypropoxy)-4-fluorobenzo[d][1,2,3]thiadiazole-6- carboxamide 21

N-(4-fluoro-5-((2-fluoro-4- iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide 22

1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2- fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide 23

N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d][1,2,3]thiadiazol-6- yl)cyclopropanesulfonamide 24

N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d][1,2,3]thiadiazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide 25

4-fluoro-5-((2-fluoro-4-bromophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6- carboxamide 26

4-fluoro-5-((2-fluoro-4- trifluoromethylphenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6- carboxamide 27

4-fluoro-5-((2-fluoro-4- methylthiophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6- carboxamide 28

5-((4-trifluoromethoxy-2- chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6- carboxamide 29

5-((2-fluoro-4-iodophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide 30

5-((4-bromo-2-fluorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide 31

5-((4-bromo-2-chlorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide 32

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-cyclopropylmethyl-benzo[d]oxazole-6- carboxamide 33

4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-cyclopropylmethyl-benzo[d]oxazole-6- carboxamide 34

4-fluoro-5-((2-fluoro-4-bromophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazol-6- carboxamide 35

4-fluoro-5-((2-fluoro-4- trifluoromethylphenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazol-6- carboxamide 36

4-fluoro-5-((2-fluoro-4- methylthiophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazol-6- carboxamide 37

5-((4-trifluoromethoxy-2- chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]thiazol-6- carboxamide 38

5-((2-fluoro-4-iodophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4-fluorobenzo[d]thiazol-6-carboxamide 39

5-((4-bromo-2-fluorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4-fluorobenzo[d]thiazol-6-carboxamide 40

5-((4-bromo-2-chlorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4-fluorobenzo[d]thiazol-6-carboxamide 41

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-cyclopropylmethyl-benzo[d]thiazol-6- carboxamide 42

4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-cyclopropylmethyl-benzo[d]thiazol-6- carboxamide 43

5-((4-bromo-2-fluorophenyl)amino)-4-fluoro- N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6- carboxamide 44

4-fluoro-5-((2-fluoro-4- trifluoromethylphenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6- carboxamide 45

4-fluoro-5-((2-fluoro-4- methylthiophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6- carboxamide 46

5-((4-trifluoromethoxy-2- chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6- carboxamide 47

5-((2-fluoro-4-iodophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4-fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide 48

5-((4-bromo-2-fluorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4-fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide 49

5-((4-bromo-2-chlorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4-fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide 50

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-cyclopropylmethyl-benzo[d][1,2,3]thiadiazol- 6-carboxamide 51

4-fluoro-5-((4-bromo-2-chlorophenyl)amino)- N-cyclopropylmethyl-benzo[d][1,2,3]thiadiazol-6-carboxamide

Compounds detailed herein may be present as salts even if salts are notdepicted and it is understood that the invention embraces all salts andsolvates (e.g., hydrate) of the compounds depicted here, as well as thenon-salt and non-solvate form of the compound, as is well understood bythe skilled artisan. In some embodiments, the salts of the compounds ofthe invention are pharmaceutically acceptable salts.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and are oftenformed during the process of crystallization. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Polymorphs include the different crystal packing arrangementsof the same elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature may cause asingle crystal form to dominate.

The compounds depicted herein may have more than one stereoisomer, andoccur as racemates, racemic mixtures where one enantiomer may beenriched, individual diastereomers, and mixtures of stereoisomers. Allstereoisomers, including enantiomers and diastereomers are embraced bythe present invention. Stereoisomers may be separated by methods knownin the art. Compositions comprising compounds detailed herein wherestereoisomers may exist may contain one pure stereomer or more than onestereoisomer where the stereoisomers are present in equal amounts orwhere some of the stereoisomers are enriched relative to the others.

The present invention includes within its scope prodrugs of thecompound, such as the compound of the formula (I), (J), (K), (A-I) orany variations thereof. In general, such prodrugs are functionalderivatives of the compound, such as functional derivatives of thecompound of the formula (I), (J), (K), (A-I) or any variations thereof,which are readily convertible in vivo into the required compound of theformula (I), (J), (K), (A-I) or any variations thereof. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in “Prodrugs: Challenges andRewards”, ed. V. J. Stella et al, Springer, 2007. A prodrug may be apharmacologically inactive derivative of a biologically active substance(the “parent drug” or “parent molecule”) that requires transformationwithin the body in order to release the active drug, and that hasimproved delivery properties over the parent drug molecule. Thetransformation in vivo may be, for example, as the result of somemetabolic process, such as chemical or enzymatic hydrolysis of acarboxylic, phosphoric or sulfuric ester, or reduction or oxidation of asusceptible functionality. In some embodiments, a prodrug for a compoundcontaining a hydroxy group may be an ester formed with an appropriateacid, such as lactic acid, citric acid, ascorbic acid, and the like.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. Unlessotherwise stated, “substantially pure” intends a composition thatcontains no more than 30% impurity, wherein the impurity denotes acompound other than the compound comprising the majority of thecomposition or a salt thereof. In some embodiments, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains no more than about 30%, about 25%, about 20%, about15%, about 10%, about 5%, about 3% or about 1% impurity.

In one aspect, provided are kits comprising a compound detailed herein,or a salt, prodrug or solvate thereof, and suitable packaging. In oneembodiment, a kit further comprises instructions for use. In one aspect,a kit comprises a compound detailed herein, such as a compound of theformula (I), (J), (K), (A-I) or any variations thereof, or a salt,prodrug or solvate thereof, and instructions for use of the compounds inthe treatment or prevention of a disease or condition which can beameliorated by inhibition of MEK in an individual in need thereof.

Articles of manufacture comprising a compound detailed herein, or asalt, prodrug or solvate thereof, in a suitable container are provided.The container may be a vial, jar, ampoule and the like.

Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to the formulae herein.

Common organic solvents can be used in the following synthesis schemes.Typical solvents include, but not limited to, aliphatic and aromatichydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleumether, petrol, benzine, benzene, toluene, xylene), aliphatic andaromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane,chloroform, phenixin, chlorobenzene, o-dichlorobenzene), alcohols (suchas methanol, ethanol, propan-1-ol, isopropanol, t-butanol,ethane-1,2-diol), ether (such as diethyl ether, dibutyl ether, glycoldimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone(such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methylisobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile(such as acetonitrile, propiononitrile), amide (such asN,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU and so on.

General Synthesis of Compounds of Formula (I)

The compound of the formula (I) where X¹ is N, X² is S, R⁶ is—C(O)NHOR⁷, and R³ is halo can be synthesized according to Scheme 1,wherein R¹, R², R⁴, R⁵ and R⁷ are as defined for the formula (J), (I) orany variations thereof; and each R¹⁴ and R¹⁵ is independently allyl,benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or—SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected fromC₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The steps in Scheme 1 are illustrated further by an exemplary synthesisof 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide, according to thereactions outlined in Scheme 1.1.

Step 1.1.1

To a solution of 2,3,4-trifluorobromobenzene in appropriate solvent isadded strong base (such as LDA, nBuLi, LiHDMS) under nitrogenatmosphere. The reaction is generally carried out at low temperature(−50-−80° C., prefer −78° C.). The reaction is kept stirring for sometime (0.5-12 h, preferably select 0.5-2 h) and is added dry ice. Theresulting mixture is kept stirring for some time (3-12 h, prefer 5-10 h)and 5-bromo-2,3,4-trifluorobenzoic acid is obtained after conventionalworkup.

Typical solvents are as defined above and prefer anhydrous THF, ethylether and dioxane).

Step 1.1.2

5-Bromo-2,3,4-trifluorobenzoic acid can be reacted with halogenatedaniline (such as o-fluoroaniline, o-chloroaniline, o-bromoaniline,o-iodoaniline) under strong basic condition (such as LDA, n-BuLi,LiHDMS) in appropriate solvent. The reaction is generally carried out atlow temperature (−50-−80° C., prefer −78° C.) and normally completeswithin several hours (3-12 h, prefer 5-10 h).5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid is obtainedafter conventional workup.

Typical solvents are as defined above and prefer anhydrous THF, ethylether and dioxane).

Step 1.1.3

5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can bereacted with MeOH in the presence of SOCl₂ in appropriate solvent. Thereaction normally completes within several hours (3-12 h, prefer 5-10h). Methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate isobtained after conventional workup.

Typical solvents are as defined above and prefer methanol and ethanol.

Step 1.1.4

To a solution of methyl5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate in appropriatesolvent is added base under nitrogen atmosphere, followed by Pdcatalyst, phosphine ligand and phenylmethanethiol. The reaction isgenerally carried out at high temperature (80-130° C., prefer 90-110°C.) and normally complete within several hours (8-24 h, prefer 12-18 h).Methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate isobtained after conventional workup.

Typical bases include, but are not limited to, aliphatic and aromaticamine (such as, but not limited to, N-ethyl-N-isopropylpropan-2-amine,triethylamine, diethylamine, DBU, t-butylamine, cyclopropanamine,dibutylamine, diisopropylamine, 1,2-dimethylpropanamine), inorganic base(such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa, ^(t)BuOK) and preferN-ethyl-N-isopropylpropan-2-amine.

Typical Pd catalysts include, but are not limited to,tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, bis(triphenylphosphine)palladium(II) chloride, palladiumdiacetate, tetrakis(triphenylphosphine)palladium,bis(triphenylphosphinepalladium)acetate and preferably selecttris(dibenzylideneacetone)dipalladium.

Typical phosphine ligands include, but are not limited to,dimethylbisdiphenylphosphinoxanthene, tri-tert-butylphosphine,tri-p-tolylphosphine, tris(4-chlorophenyl)phosphine,triisopropylphosphine, tris(2,6-dimethoxyphenyl)phosphine,1,1′-bis(diphenylphosphino)ferrocene and preferably selectdimethylbisdiphenylphosphinoxanthene.

Typical solvents are as defined above and prefer dioxane.

Step 1.1.5

Methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate canbe reacted with azide (such as NaN₃, KN₃) in appropriate solvent. Thereaction is generally carried out at high temperature (60-120° C.,prefer 80-100° C.) and normally completes within several hours (1-12 h,prefer 3-10 h). Methyl 4-azido-5-(benzylthio)-3-fluorofluorophenyl)amino)benzoate is obtained after conventional workup.

Typical solvents are as defined above and prefer N,N-dimethylformamideand N,N-dimethylacetamide.

Step 1.1.6

Methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoatecan be hydrogenated in the presence of appropriate catalyst (such asPd/C, Pt, Ni) in appropriate solvent. The reaction normally completeswithin several hours (1-12 h, prefer 3-10 h). Methyl4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate isobtained after conventional workup.

Typical solvents are as defined above and prefer methanol, ethanol,propan-1-ol and water.

Step 1.1.7

Methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylatecan be readily prepared by cyclization of methyl4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate in thepresence of inorganic acid and alkali nitrite in the appropriatesolvent.

Said inorganic acids include, but are not limited to, hydrochloric acid,sulfuric acid, nitric acid and phosphoric acid.

Said alkali nitrite includes, but is not limited to, sodium nitrite,potassium nitrite and cesium nitrite.

Typical solvents are as defined above and prefer organic acid such as,but not limited to acetic acid and formic acid.

Step 1.1.8

Methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylatecan be reacted with halogenations reagent (such as NIS) in the presenceof acid at ambient temperature in appropriate solvent. The reactionnormally completes within several hours (1-12 h, prefer 3-10 h). Methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylateis obtained after conventional workup.

Typical acids include, but are not limited to, trifluoroacetic acid,trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, andacetic acid.

Typical solvents are as defined above and prefer N,N-dimethylformamideand N,N-dimethylacetamide.

Step 1.1.9

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid can be prepared from methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylatebe deprotection in appropriate solvent.

Typical deprotection reagents may be base, Pd/C, Lewis acid or R₄NF.

Said base includes, but are not limited to, NaOH, KOH, Na₂CO₃, K₂CO₃.

Said Lewis acids include, but are not limited to AlCl₃, BF₃ and BBr₃.

Typical solvents are as defined above and prefer dichloromethane, THF,MeOH and DMF.

Step 1.1.10

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in thepresence of coupling reagent in appropriate solvent. The reaction isgenerally carried out at ambient temperature and normally completewithin several hours (1-12 h, prefer 3-10 h).4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamideis obtained after conventional workup.

Coupling reagents include, but are not limited to, HOBt, EDCI, HATU andTBTU.

Typical solvents are as defined above and prefer dichloromethane,1,2-dichloroethane and N,N-dimethylformamide.

Step 1.1.11

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamidecan be reacted under acidic condition in appropriate solvent. Thereaction normally completes within (1-12 h, prefer 3-10 h).4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamideis obtained after conventional workup.

Typical acids include, but are not limited to, hydrochloric acid,sulfuric acid and trifluoroacetic acid.

Typical solvents are as defined above and prefer dichloromethane and1,2-dichloroethane.

A compound of the formula (I-1-a), i.e., a compound of the formula (I)where X¹ is N, X² is S and R⁶ is —C(O)N(R⁸)OR⁷, where R³ is halo may besynthesized according to Scheme X-1, wherein R¹, R², R⁴, R⁵, R⁷ and R⁸are as defined for the formula (J), (I) or any variations thereof; eachR¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 3methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ areindependently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl, and X isfluoro, chloro, bromo or iodo.

Step 1:

The compound of formula (I-1-a) can be prepared from the reaction of thecompound of formula (X-II) with hydroxylamine (R⁷OR⁸NH) in the presenceof coupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to1-Hydroxy-1H-benzotriazole (HOBt),3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI),0-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU) andO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU).

Typical solvents are as defined above and prefer dichloromethane,1,2-dichloroethane, THF and N,N-dimethylformamide.

Step 2:

The compound of formula (X-II) can be prepared from deprotection of thecompound of formula (X-III) in appropriate solvent.

Typical deprotection reagents may be base, Pd/C, Lewis acid or R₄NFaccording to different R¹⁴.

Said base includes, but are not limited to, NaOH, KOH, Na₂CO₃, K₂CO₃.

Said Lewis acids include, but are not limited to AlCl₃, BF₃ and BBr₃.

Typical solvents are as defined above and prefer dichloromethane, THF,MeOH and DMF.

Step 3:

The compound of formula (X-III) where R³ is halo can be prepared fromhalogenation of the compound of formula (X-IV) in the presence ofhalogenation reagents and acid in appropriate solvent.

Typical halogenation reagents include, but are not limited to NCS, NBS,MS and so on.

Typical acids include, but are not limited to, trifluoroacetic acid,trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, andacetic acid.

Typical solvents are as defined above and prefer CH₂Cl₂, CHCl₃,N,N-dimethylformamide and N,N-dimethylacetamide.

Step 4:

The compound of formula (X-IV) can be prepared from cyclization of thecompound of formula (X-V) in the presence of diazotization reagents(such as inorganic acid and alkali nitrite) in appropriate solvent.

Typical inorganic acids include, but are not limited to, hydrochloricacid, sulfuric acid, nitric acid and phosphoric acid.

Typical alkali nitrite includes, but is not limited to, sodium nitrite,potassium nitrite and cesium nitrite.

Typical solvents are as defined above and prefer organic acid such as,but not limited to acetic acid and formic acid.

Step 5:

The compound of formula (X-V) can be prepared from reduction of thecompound of formula (X-VI) in the presence of reduction reagents inappropriate solvent.

Typical reduction reagents include, but are not limited to hydrogenationcatalyst, SnCl₂, PPh₃, NaBH₄, BH₃ and Raney Ni.

Typical solvents are as defined above and prefer methanol, ethanol,ethyl acetate and THF.

Step 6:

The compound of formula (X-VI) can be prepared from reaction of thecompound of formula (X-VII) with azide in appropriate solvent.

Typical azides prefer alkali azide, such as but not limited to NaN₃ andKN₃

Typical solvents are as defined above and prefer DMSO,N,N-dimethylformamide and N,N-dimethylacetamide.

Step 7:

The compound of formula (X-VII) can be prepared from the reaction of thecompound of formula (X-VIII) with mercaptan (R¹⁵SH) in the presence ofbase, phosphine ligand and catalyst in appropriate solvent.

Typical bases include, but are not limited to, aliphatic and aromaticamine (such as, but not limited to, N-ethyl-N-isopropylpropan-2-amine,triethylamine, diethylamine, DBU, t-butylamine, cyclopropanamine,dibutylamine, diisopropylamine, 1,2-dimethylpropanamine), inorganic base(such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa, ^(t)BuOK) and preferN-ethyl-N-isopropylpropan-2-amine.

Typical catalysts prefer Pd catalysts, such as, but are not limited to,tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, bis(triphenylphosphine)palladium(II) chloride, palladiumdiacetate, tetrakis(triphenylphosphine)palladium,bis(triphenylphosphinepalladium)acetate and preferably selecttris(dibenzylideneacetone)dipalladium.

Typical phosphine ligands include, but are not limited to,dimethylbisdiphenylphosphinoxanthene, tri-tert-butylphosphine,tri-p-tolylphosphine, tris(4-chlorophenyl)phosphine,triisopropylphosphine, tris(2,6-dimethoxyphenyl)phosphine,1,1′-bis(diphenylphosphino)ferrocene and preferably selectdimethylbisdiphenylphosphinoxanthene.

Typical solvents are as defined above and prefer dioxane.

Step 8:

The compound of formula (X-VIII) can be prepared from the reaction ofthe compound of formula (X-IX) with alcohol (R¹⁴OH) or halide (R¹⁴X) inthe presence of optional catalyst in appropriate solvent.

Typical catalysts are selected according to different substrates andinclude SOCl₂, sulfuric acid, inorganic base (such as NaHCO₃, KHCO₃,Na₂CO₃) and organic base (such as triethylamine andN-ethyl-N-isopropylpropan-2-amine).

Typical solvents are as defined above and prefer methanol, ethanol, THFand DMF.

Step 9:

The compound of formula (X-IX) can be prepared from the reaction of thecompound of formula (X-X) with the following compound in the presence ofstrong base in appropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi andLiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

Step 10:

The compound of formula (X-X) can be prepared from the reaction of thecompound of formula (X-XI) with CO₂ in the presence of strong base inappropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi andLiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

A compound of the formula (I-1-a) where R³ is other than halo may besynthesized according to Scheme X-2, where R¹, R², R⁴, R⁸, R⁵, R⁷ andare as defined for the formula (J), (I) or any variations thereof; andeach R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 3methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ areindependently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The synthetic scheme (X-2) for formula (I-1-a) compound wherein R³ isother than halo is similar to the Scheme (X-1) for formula (I-1-a)wherein R³ is halo. The difference between the two schemes is that thefollowing aniline is used in the synthetic scheme (X-2) and thecorresponding Step 3 is omitted.

The compound of formula (I-1-b), where R¹, R², X³, X⁴, X⁵, X⁷ and R⁸ areas defined for the formula (J), (I) or any variations thereof, isprepared according to the method outlined in the following scheme:

The compound of formula (I-1-b) can be prepared from the reaction of thecompound of formula (X-II) with alcohol (R⁷OH) in the presence ofcoupling reagents or with halide (R⁷X) in the presence of base inappropriate solvent.

Typical coupling reagents include, but are not limited to1-Hydroxy-1H-benzotriazole (HOBt),3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI),O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU) andO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU).

Typical solvents are as defined above and prefer dichloromethane,chloroform and THF.

The compound of formula (I-1-c), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ areas defined for the formula (J), (I) or any variations thereof, isprepared according to the method outlined in the following scheme:

The compound of formula (I-1-c) can be prepared from the reaction of thecompound of formula (X-II) with amine (R⁸R⁷NH) in the presence ofcoupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to1-Hydroxy-1H-benzotriazole (HOBt),3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI),O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU) andO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU).

Typical solvents are as defined above and prefer dichloromethane,chloroform and THF.

The compound of formula (I-1-d), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ areas defined for the formula (J), (I) or any variations thereof, isprepared according to the method outlined in the following scheme:

Step 1:

The compound of formula (I-1-d) can be prepared from the compound offormula (X-XII) in the presence of base in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such asNa₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base(such as diethylamine, triethylamine, pyridine and potassiumtrimethylsilanolate) and prefer potassium trimethylsilanolate.

Typical solvents are as defined above and prefer THF.

Step 2:

The compound of formula (XII) can be prepared from the reaction of thecompound of formula (XIII) with R⁷SO₂X (wherein X is fluoro, chloro,bromo and iodo) in the presence of base and catalyst in appropriatesolvent.

Typical bases include, but are not limited to, inorganic base (such asNa₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base(such as diethylamine, triethylamine and pyridine) and prefertriethylamine.

Typical catalysts include, but are not limited to4-dimethylaminopyridine (DMAP).

Typical solvents are as defined above and prefer dichloromethane andchloroform.

Step 3:

The compound of formula (X-XIII) can be prepared from the reaction ofthe compound of formula (X-II) with azide in the presence of base inappropriate solvent.

Typical bases include, but are not limited to, inorganic base (such asNa₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base(such as diethylamine, triethylamine and pyridine) and prefertriethylamine.

Typical azides include diphenyl phosphoryl azide (DPPA) and ethylcarbonochloridate/NaN₃ and prefer diphenyl phosphoryl azide (DPPA).

Typical solvents are as defined above and prefer t-BuOH.

In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, benzylsubstituted with 1-3 methoxy, C₁-C₄ alkyl or —SiR¹⁶R¹⁷R¹⁸ wherein eachof R¹⁶, R¹⁷ and R¹⁸ is independently selected from C₁-C₆ alkyl andC₆-C₁₀ aryl. In some embodiments, each R¹⁴ and R¹⁵ is independentlybenzyl, benzyl substituted with 1 to 2 methoxy, C₁-C₄ alkyl, t-BuMe₂Si,Ph₃Si, Et₃Si, n-Pr₃Si or i-Pr₃Si. In some embodiments, each R¹⁴ and R¹⁵is independently benzyl, o-methoxybenzyl, m-methoxybenzyl,p-methoxybenzyl or C₁-C₂ alkyl. In some embodiments, each R¹⁴ and R¹⁵ isindependently benzyl, p-methoxybenzyl or methyl.

The compound of the formula (I) where X¹ is CR¹¹, X² is O, R⁶ is—C(O)NHOR⁷, and R³ is halo can be synthesized according to Scheme 2,wherein R¹, R², R⁴, R⁵, R⁷, and R¹¹ are as defined for the formula (J),(I) or any variations thereof; R¹⁴ is hydrogen, allyl or R¹³; and eachR¹² and R¹³ is independently benzyl, benzyl substituted with 1 to 3methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ areindependently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The steps in Scheme 2 are illustrated further by an exemplary synthesisof 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide, according to the reactionsoutlined in Scheme 2.1.

Step 2.1.1

2,3,4-Trifluorophenol can be protected with hydroxy protection reagent(such as BnBr, BnCl) in the presence of base in appropriate inertsolvent. The reaction generally is carried out at ambient temperatureand normally completes within several hours (3-12 h, prefer 5-10 h).1-(Benzyloxy)-2,3,4-trifluorobenzene is obtained after conventionalworkup.

Typical bases include Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, t-BuOK and t-BuONa.

Typical solvents are as defined above and prefer acetone and methylethyl ketone.

Step 2.1.2

To a solution of 1-benzyloxy-2,3,4-trifluorobenzene in appropriate inertsolvent is added strong base (such as LDA, n-BuLi, LiHDMS) at lowtemperature (−50-−80° C., prefer −78° C.) under nitrogen atmosphere. Thestirring is maintained at this temperature for several hours (0.5-12 h,prefer 0.5-2 h). The mixture is transferred to a bottle with dry ice andthe resulting mixture is stirred for some time (such as 3-12 h, prefer5-10 h). 5-Benzoxy-2,3,4-trifluorobenzoic acid is obtained afterconventional workup.

Typical solvents are as defined above and prefer tetrahydrofuran.

Step 2.1.3

5-Benzoxy-2,3,4-trifluorobenzoic acid can be reacted with halogenatedaniline (such as o-fluoroaniline, o-chloroaniline, o-bromoaniline,o-iodoaniline) in the presence of strong base (such as LDA, n-BuLi,LiHDMS). The reaction generally is carried out at low temperature (−50°C.-−80° C., prefer −78° C.) and normally completes within several hours(3-12 h, prefer 5-10 h).5-(Benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid isobtained after conventional workup.

Step 2.1.4

5-(Benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can beprotected by protection reagent of acid or hydroxyl (such as BnBr, BnCl)under basic condition in appropriate inert solvent The reaction normallycomplete within several hours (3-12 h, prefer 5-10 h). Benzyl5-(benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtainedafter conventional workup.

Typical bases include, but are not limited to, Na₂CO₃, K₂CO₃, NaHCO₃,KHCO₃, tBuOK, and tBuONa.

Typical solvents are as defined above and prefer acetone and methylethyl ketone.

Step 2.1.5

Benzyl 5-(benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate canbe reacted with azide (such as NaN₃, KN₃) in appropriate solvent. Thereaction generally is carried out at high temperature (60-120° C.,prefer 80-100° C.) and normally completes within several hours (1-12 h,prefer 3-10 h). The desired product is obtained after conventionalworkup.

Typical solvents are as defined above and prefer N,N-dimethylformamideand N,N-dimethylacetamide.

Step 2.1.6

Benzyl 4-azido-5-(benzyloxy)-3-fluoro-2-((2-fluorophenyl)amino)benzoatecan be hydrogenated in the presence of appropriate catalyst (such asPd/C, Pt, Ni). The reaction normally completes within several hours(1-12 h, prefer 3-10 h).4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid isobtained after conventional workup.

Typical solvents are as defined above and prefer methanol, ethanol,propan-1-ol and water.

Step 2.1.7

4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid can becyclized by trialkoxymethane in the presence of acid in appropriatesolvent. The reaction normally completes within several hours (0.2-12 h,prefer 3-10 h). 4-Fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid is obtained afterconventional workup.

Said trialkoxymethane includes, but are not limited to,trimethoxymethane and triethoxymethane.

Typical acids include p-toluenesulfonic acid, pyridiniumtoluene-4-sulphonate, formic acid, acetic acid and sulfuric acid.

Typical solvents are as defined above and prefer methyl acetate, ethylacetate and trimethoxymethane.

Step 2.1.8

4-Fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid canbe reacted with halogenations reagent (such as NIS) under acidiccondition in appropriate solvent. The reaction generally is carried outat ambient temperature and normally completes within several hours (1-12h, prefer 3-10 h).4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylicacid is obtained after conventional workup.

Typical acids include, but are not limited to, trifluoroacetic acid,trifluoromethanesulfonic acid, methanesulfonic acid, formic acid andacetic acid.

Typical solvents are as defined above and prefer N,N-dimethylformamideand N,N-dimethylacetamide.

Step 2.1.9

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylicacid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in thepresence of coupling reagent in appropriate solvent. The reaction isgenerally carried out at ambient temperature and normally completewithin several hours (1-12 h, prefer 3-10 h).4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamideis obtained after conventional workup.

Coupling reagents include, but are not limited to, HOBt, EDCI, HATU andTBTU.

Typical solvents are as defined above and prefer dichloromethane,1,2-dichloroethane and N,N-dimethylformamide.

Step 2.1.10

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamidecan be reacted under acidic condition in appropriate solvent. Thereaction normally completes within (1-12 h, prefer 3-10 h).4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamideis obtained after conventional workup.

Typical acids include, but not limited to, hydrochloric acid, sulfuricacid and trifluoroacetic acid.

Typical solvents are as defined above and prefer dichloromethane and1,2-dichloroethane.

A compound of the formula (I-2-a), i.e., a compound of the formula (I)where X¹ is CR¹¹, X² is O and R⁶ is —C(O)N(R⁸)OR⁷, where R³ is halo maybe synthesized according to Scheme Y-1, wherein R¹, R², R⁴, R⁵, R⁷ andR⁸ are as defined for the formula (J), (I) or any variations thereof;each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 3methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ areindependently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl, and X isfluoro, chloro, bromo or iodo.

Step 1:

The compound of formula (I-2-a) can be prepared from the reaction of thecompound of formula (Y-II) with hydroxylamine (R⁷OR⁸NH) in the presenceof coupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to1-Hydroxy-1H-benzotriazole (HOBt),3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI),O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU) andO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU).

Typical solvents are as defined above and prefer dichloromethane,1,2-dichloroethane, THF and N,N-dimethylformamide.

Step 2:

The compound of formula (Y-II) where R³ is halo can be prepared fromhalogenation of the compound of formula (Y-III) in the presence ofhalogenation reagents and acid in appropriate solvent.

Typical halogenation reagents include, but are not limited to NCS, NBS,MS and so on.

Typical acids include, but are not limited to, trifluoroacetic acid,trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, andacetic acid.

Typical solvents are as defined above and prefer CH₂Cl₂, CHCl₃,N,N-dimethylformamide and N,N-dimethylacetamide.

Step 3:

The compound of formula (Y-III) where R¹¹ is hydrogen can be preparedfrom cyclization of the compound of formula (Y-IV) in the presence ofacid and tri(C₁-C₆ alkyl)orthoformate in appropriate solvent.

Typical acids include, but are not limited to p-toluenesulfonic acid,pyridinium toluene-4-sulphonate, methane sulfonic acid andbenzenesulfonic acid.

Said tri(C₁-C₆ alkyl)orthoformate includes trimethoxymethane andtriethoxymethane.

Typical solvents are as defined above and prefer MeOH, CH₂Cl₂, CHCl₃,DMSO and N,N-dimethylformamide.

The compound of formula (Y-III) where R¹¹ is other than hydrogen can beprepared from the reaction of the compound of formula (Y-IV) withsubstituted acid (R¹¹COOH) in the presence of catalyst in appropriatesolvent.

Typical catalyst includes, but is not limited to polyphosphoric acids.

Step 4:

The compound of formula (Y-IV) can be prepared from hydrogenation of thecompound of formula (Y-V) in the presence of catalyst in appropriatesolvent.

Typical hydrogenation catalysts include, but are not limited to Pd/C, Ptand Ni.

Typical solvents are as defined above and prefer methanol, ethanol andTHF.

Step 5:

The compound of formula (Y-V) can be prepared from reaction of thecompound of formula (Y-VI) with azide in appropriate solvent.

Typical azides prefer alkali azide, such as but not limited to NaN₃ andKN₃

Typical solvents are as defined above and prefer DMSO,N,N-dimethylformamide and N,N-dimethylacetamide.

Step 6:

The compound of formula (Y-VI) can be prepared from the reaction of thecompound of formula (Y-VII) with alcohol (R¹³OH) or halide (R¹³X, Xprefers Br) in the presence of acid or base in appropriate solvent.

Where the compound of formula (Y-VII) is reacted with alcohol (R¹³OH),typical acids include, but are not limited to, sulfuric acid,p-toluenesulfonic acid, pyridinium toluene-4-sulphonate andtrifluoroacetic acid.

Typical solvents are as defined above and prefer benzyl alcohol,methanol, ethanol, 1-propanol and n-butanol.

Where the compound of formula (Y-VII) is reacted with halide (R¹³X),typical bases include, but are not limited to, Na₂CO₃, K₂CO₃, NaHCO₃,KHCO₃, t-BuONa and t-BuOK.

Typical solvents are as defined above and prefer N,N-dimethylformamide,N,N-dimethylacetamide.

Step 7:

The compound of formula (Y-VII) can be prepared from the reaction of thecompound of formula (Y-VIII) with the following compound in the presenceof strong base in appropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi andLiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

Step 8:

The compound of formula (Y-VIII) can be prepared from the reaction ofthe compound of formula (Y-IX) with CO₂ in the presence of strong basein appropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi andLiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

Step 9:

The compound of formula (Y-IX) can be prepared from the reaction of thecompound of formula (Y-X) with R¹²X (X prefers bromo) in the presence ofbase in appropriate solvent.

Typical bases include, but are not limited to, Na₂CO₃, K₂CO₃, NaHCO₃,KHCO₃, t-BuONa and t-BuOK.

Typical solvents are as defined above and prefer THF, DMF and acetone.

A compound of the formula (I-2-a), i.e., a compound of the formula (I)where X¹ is CR¹¹, X² is O and R⁶ is —C(O)N(R⁸)OR⁷, where R³ is otherthan halo may be synthesized according to Scheme Y-2, wherein R¹, R²,R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or anyvariations thereof; and each R¹⁴ and R¹⁵ is independently benzyl, benzylsubstituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl andC₆-C₁₄ aryl.

The synthetic scheme (Y-2) for compound of the formula (I-2-a) whereinR³ is other than halo is similar to the scheme (Y-1) for formula (I-2-a)wherein R³ is halo. The difference between the two schemes is that thefollowing aniline is used in the synthetic scheme (A-2) and thecorresponding Step 2 is omitted.

The compound of formula (I-2-b), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ areas defined for the formula (J), (I) or any variations thereof, isprepared according to the method outlined in the following scheme:

The compound of formula (I-2-b) can be prepared from the reaction of thecompound of formula (Y-II) with alcohol (R⁷OH) in the presence ofcoupling reagents or with halide (R⁷X) in the presence of base inappropriate solvent.

Typical coupling reagents include, but are not limited to1-Hydroxy-1H-benzotriazole (HOBt),3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI),O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU) andO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU).

Typical solvents are as defined above and prefer dichloromethane,chloroform and THF.

The compound of formula (I-2-c), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ areas defined for the formula (J), (I) or any variations thereof, isprepared according to the method outlined in the following scheme:

The compound of formula (I-2-c) can be prepared from the reaction of thecompound of formula (Y-II) with amine (R⁸R⁷NH) in the presence ofcoupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to1-Hydroxy-1H-benzotriazole (HOBt),3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI),O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU) andO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU).

Typical solvents are as defined above and prefer dichloromethane,chloroform and THF.

The compound of formula (I-2-d), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ areas defined for the formula (J), (I) or any variations thereof, isprepared according to the method outlined in the following scheme:

Step 1:

The compound of formula (I-2-d) can be prepared from the compound offormula (Y-XI) in the presence of base in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such asNa₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base(such as diethylamine, triethylamine, pyridine and potassiumtrimethylsilanolate) and prefer potassium trimethylsilanolate.

Typical solvents are as defined above and prefer THF and CH₂Cl₂.

Step 2:

The compound of formula (Y-XI) can be prepared from the reaction of thecompound of formula (Y-XII) with R⁷SO₂X (wherein X is fluoro, chloro,bromo and iodo) in the presence of base and catalyst in appropriatesolvent.

Typical bases include, but are not limited to, inorganic base (such asNa₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base(such as diethylamine, triethylamine and pyridine) and prefertriethylamine.

Typical catalysts include, but are not limited to4-dimethylaminopyridine (DMAP).

Typical solvents are as defined above and prefer dichloromethane andchloroform.

Step 3:

The compound of formula (Y-XII) can be prepared from the reaction of thecompound of formula (Y-II) with azide in the presence of base inappropriate solvent.

Typical bases include, but are not limited to, inorganic base (such asNa₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base(such as diethylamine, triethylamine and pyridine) and prefertriethylamine.

Typical azides include diphenyl phosphoryl azide (DPPA) and ethylcarbonochloridate/NaN₃ and prefer diphenyl phosphoryl azide (DPPA).

Typical solvents are as defined above and prefer t-BuOH.

In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, benzylsubstituted with 1-3 methoxy, C₁-C₄ alkyl or —SiR¹⁶R¹⁷R¹⁸, wherein eachof e, R¹⁷ and R¹⁸ is independently selected from C₁-C₆ alkyl and C₆-C₁₀aryl. In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl,benzyl substituted with 1 to 2 methoxy, C₁-C₄ alkyl, t-BuMe₂Si, Ph₃Si,Et₃Si, n-Pr₃Si or i-Pr₃Si. In some embodiments, each R¹⁴ and R¹⁵ isindependently benzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzylor C₁-C₂ alkyl. In some embodiments, each R¹⁴ and R¹⁵ is independentlybenzyl, p-methoxybenzyl or methyl.

The compound of the formula (I) where X¹ is CR¹¹, X² is R⁶, is—C(O)NHOR⁷, and R³ is halo can be synthesized according to Scheme 3,wherein R¹, R², R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula (J),(I) or any variations thereof; R¹⁴ is hydrogen, allyl or R¹³; and eachR¹² and R¹³ is independently benzyl, benzyl substituted with 1 to 3methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ areindependently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The steps in Scheme 3 are illustrated further by an exemplary synthesisof 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide, according to the reactionsoutlined in Scheme 3.1.

Step 3.1.1

To a solution of 2,3,4-trifluorobromobenzene in appropriate solvent isadded strong base (such as LDA, nBuLi, LiHDMS) under nitrogenatmosphere. The reaction is generally carried out at low temperature(−50-−80° C., prefer −78° C.). The reaction is kept stirring for sometime (0.5-12 h, preferably select 0.5-2 h) and is added dry ice. Theresulting mixture is kept stirring for some time (3-12 h, prefer 5-10 h)and 5-bromo-2,3,4-trifluorobenzoic acid is obtained after conventionalworkup.

Typical solvents are as defined above and prefer anhydrous THF, ethylether and dioxane).

Step 3.1.2

5-Bromo-2,3,4-trifluorobenzoic acid can be reacted with halogenatedaniline (such as o-fluoroaniline, o-chloroaniline, o-bromoaniline,o-iodoaniline) under strong basic condition (such as LDA, n-BuLi,LiHDMS) in appropriate solvent. The reaction is generally carried out atlow temperature (−50-−80° C., prefer −78° C.) and normally completeswithin several hours (3-12 h, prefer 5-10 h).5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid is obtainedafter conventional workup.

Typical solvents are as defined above and prefer anhydrous THF, ethylether and dioxane).

Step 3.1.3

5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can bereacted with MeOH in the presence of SOCl₂ in appropriate solvent. Thereaction normally completes within several hours (3-12 h, prefer 5-10h). Methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate isobtained after conventional workup.

Typical solvents are as defined above and prefer methanol and ethanol.

Step 3.1.4

To a solution of methyl5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate in appropriatesolvent is added base under nitrogen atmosphere, followed by Pdcatalyst, phosphine ligand and (4-methoxyphenyl)methanethiol. Thereaction is generally carried out at high temperature (80-130° C.,prefer 90-110° C.) and normally complete within several hours (8-24 h,prefer 12-18 h). Methyl3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoateis obtained after conventional workup.

Typical bases include, but are not limited to, aliphatic and aromaticamine (such as, but not limited to, N-ethyl-N-isopropylpropan-2-amine,triethylamine, diethylamine, DBU, t-butylamine, cyclopropanamine,dibutylamine, diisopropylamine, 1,2-dimethylpropanamine), inorganic base(such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa, ^(t)BuOK) and preferN-ethyl-N-isopropylpropan-2-amine.

Typical Pd catalysts include, but are not limited to,tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, bis(triphenylphosphine)palladium(II) chloride, palladiumdiacetate, tetrakis(triphenylphosphine)palladium,bis(triphenylphosphinepalladium)acetate and preferably selecttris(dibenzylideneacetone)dipalladium.

Typical phosphine ligands include, but are not limited to,dimethylbisdiphenylphosphinoxanthene, tri-tert-butylphosphine,tri-p-tolylphosphine, tris(4-chlorophenyl)phosphine,triisopropylphosphine, tris(2,6-dimethoxyphenyl)phosphine,1,1′-bis(diphenylphosphino)ferrocene and preferably selectdimethylbisdiphenyl phosphinoxanthene.

Typical solvents are as defined above and prefer dioxane.

Step 3.1.5

Methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate can be reacted with azide (such as NaN₃, KN₃) inappropriate solvent. The reaction is generally carried out at hightemperature (60-120° C., prefer 80-100° C.) and normally completeswithin several hours (1-12 h, prefer 3-10 h). Methyl4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoateis obtained after conventional workup.

Typical solvents are as defined above and prefer N,N-dimethylformamideand N,N-dimethylacetamide.

Step 3.1.6

Methyl 4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate can be hydrogenated in the presence of appropriatecatalyst (such as Pd/C, Pt, Ni) in appropriate solvent. The reactionnormally completes within several hours (1-12 h, prefer 3-10 h). Methyl4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoateis obtained after conventional workup.

Typical solvents are as defined above and prefer methanol, ethanol,propan-1-ol and water.

Step 3.1.7

5,5′-Disulfanediylbis(4-amino-3-fluoro-2-((2-fluorophenyl)amino)benzoate)can be prepared from methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate by deprotection inappropriate solvent. The desired product is obtained after conventionalworkup.

Typical deprotection reagents may be acid, Pd/C, Lewis acid or R₄NFaccording to R¹⁵.

Said acid includes, but are not limited to, CF₃COOH.

Said Lewis acid includes, but is not limited to, BF₃ and BBr₃.

Said deprotection reagents include oxidative reagents such as, but arenot limited to, ammonium ceric nitrate and DDQ and prefer DDQ.

Typical solvents are as defined above and prefer dichloromethane,chloroform, MeOH and EtOH.

Step 3.1.8

5,5′-Disulfanediylbis(4-amino-3-fluoro-2-((2-fluorophenyl)amino)benzoate)can be reduced in appropriate solvent. Methyl4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate isobtained after conventional workup.

Said reductive reagents include NaBH₄, NaCNBH₃, NaBH(OAc)₃, Zn powderand Fe powder.

Typical solvents are as defined above and prefer the mixture of THF andMeOH.

Step 3.1.9

Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercapto benzoatecan be cyclized in the presence of acid in appropriate solvent. Thereaction normally completes within several hours (0.2-12 h, prefer0.5-10 h). Methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate isobtained after conventional workup.

Typical acids include, but are not limited to p-toluenesulfonic acid,pyridinium toluene-4-sulphonate, formic acid, acetic acid and sulfuricacid.

Typical solvents are as defined above and prefer methyl acetate, ethylacetate and trimethoxymethane.

Step 3.1.10

Methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylatecan be reacted with halogenations reagent (such as NIS) in the presenceof acid at ambient temperature in appropriate solvent. The reactionnormally completes within several hours (1-12 h, prefer 3-10 h). Methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylateis obtained after conventional workup.

Typical acids include, but are not limited to, trifluoroacetic acid,trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, andacetic acid.

Typical solvents are as defined above and prefer N,N-dimethylformamideand N,N-dimethylacetamide.

Step 3.1.11

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylicacid can be prepared from methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate be deprotection inappropriate solvent.

Typical deprotection reagents may be base, Pd/C, Lewis acid or R₄NF.

Said base includes, but are not limited to, NaOH, KOH, Na₂CO₃ and K₂CO₃.

Said Lewis acids include, but are not limited to AlCl₃, BF₃ and BBr₃.

Typical solvents are as defined above and prefer dichloromethane, THF,MeOH and DMF.

Step 3.1.12

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylicacid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in thepresence of coupling reagent in appropriate solvent. The reaction isgenerally carried out at ambient temperature and normally completewithin several hours (1-12 h, prefer 3-10 h).4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamideis obtained after conventional workup.

Coupling reagents include, but are not limited to, HOBt, EDCI, HATU andTBTU.

Typical solvents are as defined above and prefer dichloromethane,1,2-dichloroethane and N,N-dimethylformamide.

Step 3.1.13

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamidecan be reacted under acidic condition in appropriate solvent. Thereaction normally completes within (1-12 h, prefer 3-10 h).4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamideis obtained after conventional workup.

Typical acids include, but not limited to, hydrochloric acid, sulfuricacid and trifluoroacetic acid.

Typical solvents are as defined above and prefer dichloromethane and1,2-dichloroethane.

A compound of the formula (I-3-a), i.e., a compound of the formula (I)where X¹ is CR¹¹, X² is S and R⁶ is —C(O)N(R⁸)OR⁷, where R³ is halo maybe synthesized according to Scheme Z-1, wherein R¹, R², R⁴, R⁵, R⁷ andR⁸ are as defined for the formula (J), (I) or any variations thereof;each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 3methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ areindependently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl, and X isfluoro, chloro, bromo or iodo.

Step 1:

The compound of formula (I-3-a) can be prepared from the reaction of thecompound of formula (Z-II) with hydroxylamine (R⁷OR⁸NH) in the presenceof coupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to1-Hydroxy-1H-benzotriazole (HOBt),3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI),O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU) andO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU).

Typical solvents are as defined above and prefer dichloromethane,1,2-dichloroethane, THF and N,N-dimethylformamide.

Step 2:

The compound of formula (Z-II) can be prepared from deprotection of thecompound of formula (Z-III) in appropriate solvent.

Typical deprotection reagents may be base, Pd/C, Lewis acid or R₄NFaccording to different R¹⁴.

Said base includes, but are not limited to, NaOH, KOH, Na₂CO₃, K₂CO₃.

Said Lewis acids include, but are not limited to AlCl₃, BF₃ and BBr₃.

Typical solvents are as defined above and prefer dichloromethane, THF,MeOH and DMF.

Step 3:

The compound of formula (Z-III) where R³ is halo can be prepared fromhalogenation of the compound of formula (Z-IV) in the presence ofhalogenation reagents and acid in appropriate solvent.

Typical halogenation reagents include, but are not limited to NCS, NBS,MS and so on.

Typical acids include, but are not limited to, trifluoroacetic acid,trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, andacetic acid.

Typical solvents are as defined above and prefer CH₂Cl₂, CHCl₃,N,N-dimethylformamide and N,N-dimethylacetamide.

Step 4:

The compound of formula (Z-IV) where R¹¹ is hydrogen can be preparedfrom cyclization of the compound of formula (Z-V) in the presence ofacid and tri(C₁-C₆ alkyl)orthoformate in appropriate solvent.

Typical acids include, but are not limited to p-toluenesulfonic acid,pyridinium toluene-4-sulphonate, methane sulfonic acid andbenzenesulfonic acid.

Said tri(C₁-C₆ alkyl)orthoformate includes trimethoxymethane andtriethoxymethane.

Typical solvents are as defined above and prefer MeOH, CH₂Cl₂, CHCl₃,DMSO and N,N-dimethylformamide.

The compound of formula (Z-IV) where R¹¹ is other than hydrogen can beprepared from the reaction of the compound of formula (Z-V) withsubstituted acid (R¹¹COOH), R¹¹C(OMe)₃ or R^(i1)C(OEt)₃ in the presenceof catalyst in appropriate solvent.

Typical catalyst includes, but is not limited to polyphosphoric acids.

Step 5:

The compound of formula (Z-V) can be prepared from the compound offormula (Z-VI) in the presence of reduction reagent in appropriatesolvent.

Typical reduction reagents include, but are not limited to NaBH₄,NaBH₃CN, NaBH(Ac)₃, Zn powder and Fe powder.

Typical solvents are as defined above and prefer the mixture of THF andMeOH.

Step 6:

The compound of formula (Z-VI) can be prepared from the compound offormula (Z-VII) in the presence of deprotection reagent in appropriatesolvent.

Typical deprotection reagents may be acid, Pd/C, Lewis acid or R₄NFaccording to R¹⁵.

Said acid includes, but are not limited to, CF₃COOH.

Said Lewis acid includes, but is not limited to, BF₃ and BBr₃.

Said deprotection reagents include oxidative reagents such as, but arenot limited to, ammonium ceric nitrate and DDQ and prefer DDQ.

Typical solvents are as defined above and prefer dichloromethane,chloroform, MeOH and EtOH.

Step 7:

The compound of formula (Z-VII) can be prepared from reduction of thecompound of formula (Z-VIII) in the presence of reduction reagents inappropriate solvent.

Typical reduction reagents include, but are not limited to hydrogenationcatalyst, SnCl₂, PPh₃, NaBH₄, BH₃ and Raney Ni.

Typical solvents are as defined above and prefer methanol, ethanol,ethyl acetate and THF.

Step 8:

The compound of formula (Z-VIII) can be prepared from reaction of thecompound of formula (Z-IX) with azide in appropriate solvent.

Typical azides prefer alkali azide, such as but not limited to NaN₃ andKN₃

Typical solvents are as defined above and prefer DMSO,N,N-dimethylformamide and N,N-dimethylacetamide.

Step 9:

The compound of formula (Z-IX) can be prepared from the reaction of thecompound of formula (Z-X) with mercaptan (R¹⁵SH) in the presence ofbase, phosphine ligand and catalyst in appropriate solvent.

Typical bases include, but are not limited to, aliphatic and aromaticamine (such as, but not limited to, N-ethyl-N-isopropylpropan-2-amine,triethylamine, diethylamine, DBU, t-butylamine, cyclopropanamine,dibutylamine, diisopropylamine, 1,2-dimethylpropanamine), inorganic base(such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuOK) and preferN-ethyl-N-isopropylpropan-2-amine.

Typical catalysts prefer Pd catalysts, such as, but are not limited to,tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, bis(triphenylphosphine)palladium(II) chloride, palladiumdiacetate, tetrakis(triphenylphosphine)palladium,bis(triphenylphosphinepalladium)acetate and preferably selecttris(dibenzylideneacetone)dipalladium.

Typical phosphine ligands include, but are not limited to,dimethylbisdiphenylphosphinoxanthene, tri-tert-butylphosphine,tri-p-tolylphosphine, tris(4-chlorophenyl)phosphine,triisopropylphosphine, tris(2,6-dimethoxyphenyl)phosphine,1,1′-bis(diphenylphosphino)ferrocene and preferably selectdimethylbisdiphenyl phosphinoxanthene.

Typical solvents are as defined above and prefer dioxane.

Step 10:

The compound of formula (Z-X) can be prepared from the reaction of thecompound of formula (Z-XI) with alcohol (R¹⁴OH) or halide (R¹⁴X) in thepresence of optional catalyst in appropriate solvent.

Typical catalysts are selected according to different substrates andinclude SOCl₂, sulfuric acid, inorganic base (such as NaHCO₃, KHCO₃,Na₂CO₃) and organic base (such as triethylamine andN-ethyl-N-isopropylpropan-2-amine).

Typical solvents are as defined above and prefer methanol and ethanol.

Step 11:

The compound of formula (Z-XI) can be prepared from the reaction of thecompound of formula (Z-XII) with the following compound in the presenceof strong base in appropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi andLiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

Step 12:

The compound of formula (Z-XII) can be prepared from the reaction of thecompound of formula (Z-XIII) with CO₂ in the presence of strong base inappropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi andLiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

A compound of the formula (I-3-a), i.e., a compound of the formula (I)where X¹ is CR¹¹, X² is S and R⁶ is —C(O)N(R⁸)OR⁷, where R³ is otherthan halo may be synthesized according to Scheme Z-2, wherein R¹, R²,R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or anyvariations thereof; and each R¹⁴ and R¹⁵ is independently benzyl, benzylsubstituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl andC₆-C₁₄ aryl.

The synthetic scheme (Z-2) of formula (I-3-a) compound wherein R³ isother than halo is similar to the scheme (Z-1) of formula (I-1) whereinR³ is halo. The difference between the two schemes is that the followinganiline is used in the synthetic scheme (Z-2) and the corresponding Step3 is omitted.

The compound of formula (I-3-b), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ areas defined for the formula (J), (I) or any variations thereof, isprepared according to the method outlined in the following scheme:

The compound of formula (I-3-b) can be prepared from the reaction of thecompound of formula (Z-II) with alcohol (R⁷OH) in the presence ofcoupling reagents or with halide (R⁷X) in the presence of base inappropriate solvent.

Typical coupling reagents include, but are not limited to1-Hydroxy-1H-benzotriazole (HOBt),3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI),O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU) andO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU).

Typical solvents are as defined above and prefer dichloromethane,chloroform and THF.

The compound of formula (I-3-c), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ areas defined for the formula (J), (I) or any variations thereof, isprepared according to the method outlined in the following scheme:

The compound of formula (I-3-c) can be prepared from the reaction of thecompound of formula (Z-II) with amine (R⁸R⁷NH) in the presence ofcoupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to1-Hydroxy-1H-benzotriazole (HOBt),3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI),O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU) andO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU).

Typical solvents are as defined above and prefer dichloromethane,chloroform and THF.

The compound of formula (I-3-d), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ areas defined for the formula (J), (I) or any variations thereof, isprepared according to the method outlined in the following scheme:

Step 1:

The compound of formula (I-3-d) can be prepared from the compound offormula (Z-XIV) in the presence of base in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such asNa₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base(such as diethylamine, triethylamine, pyridine and potassiumtrimethylsilanolate) and prefer potassium trimethylsilanolate.

Typical solvents are as defined above and prefer THF.

Step 2:

The compound of formula (Z-XIV) can be prepared from the reaction of thecompound of formula (Z-XV) with R⁷SO₂X (wherein X is fluoro, chloro,bromo and iodo) in the presence of base and catalyst in appropriatesolvent.

Typical bases include, but are not limited to, inorganic base (such asNa₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base(such as diethylamine, triethylamine and pyridine) and prefertriethylamine.

Typical catalysts include, but are not limited to4-dimethylaminopyridine (DMAP).

Typical solvents are as defined above and prefer dichloromethane andchloroform.

Step 3:

The compound of formula (Z-XV) can be prepared from the reaction of thecompound of formula (Z-II) with azide in the presence of base inappropriate solvent.

Typical bases include, but are not limited to, inorganic base (such asNa₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base(such as diethylamine, triethylamine and pyridine) and prefertriethylamine.

Typical azides include diphenyl phosphoryl azide (DPPA) and ethylcarbonochloridate/NaN₃ and prefer diphenyl phosphoryl azide (DPPA).

Typical solvents are as defined above and prefer t-BuOH.

In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, benzylsubstituted with 1-3 methoxy, C₁-C₄ alkyl or —SiR¹⁶R¹⁷R¹⁸, wherein eachof R¹⁶, R¹⁷ and R¹⁸ is independently selected from C₁-C₆ alkyl andC₆-C₁₀ aryl. In some embodiments, each R¹⁴ and R¹⁵ is independentlybenzyl, benzyl substituted with 1 to 2 methoxy, C₁-C₄ alkyl, t-BuMe₂Si,Ph₃Si, Et₃Si, n-Pr₃Si or i-Pr₃Si. In some embodiments, each R¹⁴ and R¹⁵is independently benzyl, o-methoxybenzyl, m-methoxybenzyl,p-methoxybenzyl or C₁-C₂ alkyl. In some embodiments, each R¹⁴ and R¹⁵ isindependently benzyl, p-methoxybenzyl or methyl.

The compound of the formula (I) where X¹ is N, X² is O, R⁶ is—C(O)NHOR⁷, and R³ is halo can be synthesized according to Scheme 4,wherein R¹, R², R⁴, R⁵ and R⁷ are as defined for the formula (J), (I) orany variations thereof; and each R¹² and R¹³ is independently benzyl,benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or—SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected fromC₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The steps in Scheme 4 are illustrated further by an exemplary synthesisof 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]oxadiazole-6-carboxamide, according to thereactions outlined in Scheme 4.1.

Thus, in one aspect, the invention provides methods and processes formaking a compound of the formula (J), or a salt thereof, comprisingcoupling of a compound of the formula (G), or a salt thereof, with ahydroxylamine derivative of the formula R⁷⁰—N(R⁸)H or a salt thereof:

wherein X¹, X², R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for theformula (J), (I) or any variations thereof, and R¹⁴ is hydrogen, benzyl,benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or—SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected fromC₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of theformula (J), or a salt thereof, wherein X¹ is N and X² is S, comprisingcoupling of a compound of the formula (G-1a), or a salt thereof, with ahydroxylamine derivative of the formula R⁷⁰—N(R⁸)H or a salt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula(J), (I) or any variations thereof, and R¹⁴ is hydrogen, benzyl, benzylsubstituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl andC₆-C₁₄ aryl. In some embodiments, the method further comprisesconverting a compound of the formula (F-1a) or a salt thereof to thecompound of the formula (G-1a) or a salt thereof:

wherein R¹⁵ is allyl, benzyl, benzyl substituted with 1 to 3 methoxygroups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ areindependently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl. In someembodiments, the method further comprises diazotization of the compoundof the formula (F-1a) or a salt thereof.

In some embodiments, provided is a method of making a compound of theformula (J), or a salt thereof, wherein, X¹ is CR¹¹ and X² is O,comprising coupling of a compound of the formula (G-2a), or a saltthereof, with a hydroxylamine derivative of the formula R⁷⁰—N(R⁸)H or asalt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁸ and R¹¹ are as defined for theformula (J), (I) or any variations thereof, and R¹⁴ is hydrogen, benzyl,benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or—SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected fromC₁-C₁₀ alkyl and C₆-C₁₄ aryl. In some embodiments, the method furthercomprises converting a compound of the formula (F-2a) or a salt thereofto the compound of the formula (G-2a) or a salt thereof:

In some embodiments of the method where R¹¹ is hydrogen, the methodcomprises contacting an orthoester of formic acid with the compound ofthe formula (F-2a) or a salt thereof.

In some embodiments, provided is a method of making a compound of theformula (J), or a salt thereof, wherein X¹ is CR¹¹ and X² is S,comprising coupling of a compound of the formula (G-3a), or a saltthereof, with a hydroxylamine derivative of the formula R⁷O—N(R⁸)H or asalt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁸ and R¹¹ are as defined for theformula (J), (I) or any variations thereof, and R¹⁴ is hydrogen, benzyl,benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or—SiR¹⁶R¹⁷R¹⁸ where R¹¹, R¹⁷ and R¹⁸ are independently selected fromC₁-C₁₀ alkyl and C₆-C₁₄ aryl. In some embodiments, the method furthercomprises converting a compound of the formula (F-3a) or a salt thereofto the compound of the formula (G-3a) or a salt thereof:

In some embodiments, the method further comprises converting a compoundof the formula (F-1a) or a salt thereof to the compound of the formula(F-3a) or a salt thereof:

wherein R¹⁵ is allyl, benzyl, benzyl substituted with 1 to 3 methoxygroups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ areindependently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl. In onevariation of the method, the compound of the formula (F-1a) or a saltthereof is converted to the compound of the formula (F-3a) or a saltthereof via an intermediate of the formula (F-3a′) or a salt thereof:

In some of these embodiments of the method where R¹¹ is hydrogen, themethod comprises reacting an orthoester of formic acid with a compoundof the formula (F-3a) or a salt thereof.

In some embodiments, provided is a method of making a compound of theformula (J-1a), or a salt thereof, comprising the steps according toScheme 1A:

wherein R¹, R², R³, R⁴, R⁵ and R⁷ are as defined for the formula (J),(I) or any variations thereof, provided that R³ is other than halo; andeach R¹⁴ and R¹⁵ is independently allyl, benzyl, benzyl substituted with1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ andR¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of theformula (J-1a) where R³ is halo, or a salt thereof, comprising the stepsaccording to Scheme 1B:

wherein R¹, R², R⁴, R⁵ and R⁷ are as defined for the formula (J), (I) orany variations thereof; and each R¹⁴ and R¹⁵ is independently allyl,benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or—SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected fromC₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of theformula (J-2a) or a salt thereof, comprising the steps according toScheme 2A:

wherein R¹, R², R³, R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula(J), (I) or any variations thereof, provided that R³ is other than halo;R¹⁴ is hydrogen, allyl or R¹³; and each R¹² and R¹³ is independentlybenzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or—SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected fromC₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of theformula (J-2a), where R³ is halo, or a salt thereof, comprising thesteps according to Scheme 2B:

wherein R¹, R², R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula (J),(I) or any variations thereof; R¹⁴ is hydrogen, allyl or R¹³; and eachR¹² and R¹³ is independently benzyl, benzyl substituted with 1 to 3methoxy groups, C₁-C₅ alkyl or SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ areindependently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of theformula (J-3a) or a salt thereof, comprising the steps according toScheme 3A:

wherein R¹, R², R³, R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula(J), (I) or any variations thereof, provided that R³ is other than halo;and each R¹⁴ and R¹⁵ is independently allyl, benzyl, benzyl substitutedwith 1 to 3 methoxy groups, C₁-C₅ alkyl or SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of theformula (J-3a) or a salt thereof, comprising the steps according toScheme 3A-1:

wherein R¹, R², R³, R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula(J), (I) or any variations thereof, provided that R³ is other than halo;and each R¹⁴ and R¹⁵ is independently allyl, benzyl, benzyl substitutedwith 1 to 3 methoxy groups, C₁-C₅ alkyl or SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of theformula (J-3a) where R³ is halo, or a salt thereof, comprising the stepsaccording to Scheme 3B:

wherein R¹, R², R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula (J),(I) or any variations thereof; and each R¹⁴ and R¹⁵ is independentlyallyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅alkyl or SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selectedfrom C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of theformula (J-3a) where R³ is halo, or a salt thereof, comprising the stepsaccording to Scheme 3B-1:

wherein R¹, R², R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula (J),(I) or any variations thereof; and each R¹⁴ and R¹⁵ is independentlyallyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅alkyl or SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selectedfrom C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

Further Embodiments of the Invention

In one aspect, provided herein is a compound of formula (A-I), or apharmaceutically accepted salt, prodrug or solvate thereof:

wherein:

each of R¹, R², R⁴ and R⁵ is independently H, halogen, nitro, azido,—OR⁷, —C(O)R⁷, —C(O)OR⁷, —NR⁸C(O)OR¹⁶, —OC(O)R⁷—SO₂NR⁷R⁸, —NR⁸C(O)R⁷,—C(O)NR⁷R⁸, —NR⁹C(O)NR⁷R⁸, —NR⁹C(NCN)NR⁷R⁸, —NR⁷R⁸, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)alkyl,—S(O)_(j)(C₁-C₁₀ alkyl), —S(O)_(j)(CR⁸R⁹)_(m), C₆-C₁₄ aryl, C₆-C₁₄arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁸R⁹)_(m)-aryl, —NR⁸(CR⁸R⁹)_(m)-aryl, —O(CR⁸R⁹)_(m)-heteroaryl,—NR⁸(CR⁸R⁹)_(m)-heteroaryl, —O(CR⁸R⁹)_(m)-heterocyclyl, or—NR⁸(CR⁸R⁹)_(m)-heterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl is optionally substituted with one or more groupsindependently selected from oxo-, halogen, cyano, nitro, —CF₃, azido,—OR⁷, —C(O)R⁷, —C(O)OR⁷, —NR⁸C(O)OR¹⁰, —OC(O)R⁷, —NR⁸SO₂R¹⁰, —SO₂NR⁷R⁸,—NR⁸C(O)R⁷, —C(O)NR⁷R⁸, —NR⁹C(O)NR⁷R⁸, —NR⁹C(NCN)NR⁷R⁸, —NR⁷R⁸, C₆-C₁₄aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, heteroaryl(C₁-C₁₀ alkyl),heterocycloalkyl, and heterocycloalkyl(C₁-C₁₀ alkyl);

R³ is H, halogen, cyano, nitro, azido, —OR⁷, —SR′, —C(O)R⁷, —C(O)OR⁷,—NR⁸C(O)OR¹⁰, —OC(O)R⁷, —NR⁸SO₂R¹⁰, —SO₂NR⁷R⁸, —NR⁸C(O)R⁷, —C(O)NR⁷R⁸,—NR⁹C(O)NR⁷R⁸, —NR⁹C(NCN)NR⁷R⁸, —NR⁷R⁸, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl,—S(O)_(j)(C₁-C₁₀ alkyl), —S(O)_(j)(CR⁸R⁹)_(m)C₆-C₁₄ aryl, (C₆-C₁₄aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl,heterocycloalkyl, (heterocycloalkyl)C₁-C₁₀ alkyl, —O(CR⁸R⁹)_(m)-aryl,—NR⁸(CR⁸R⁹)_(m)-aryl, —O(CR⁸R⁹)_(m)-heteroaryl,—NR⁸(CR⁸R⁹)_(m)-heteroaryl, —O(CR⁸R⁹)_(m)— heterocyclyl, or—NR⁸(CR⁸R⁹)_(m)-heterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl portions is optionally substituted with one or moregroups independently selected from oxo-, halogen, cyano, nitro, —CF₃,azido, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —NR⁸C(O)OR¹⁰, —OC(O)R⁷, —NR⁸SO₂R¹⁰,—SO₂NR⁷R⁸, —NR⁸C(O)R⁷, —C(O)NR⁷R⁸, —NR⁹C(O)NR⁷R⁸, —NR⁹C(NCN)NR⁷R⁸,—NR⁷R⁸, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl,heteroaryl(C₁-C₁₀ alkyl), heterocycloalkyl, and heterocycloalkyl(C₁-C₁₀alkyl);

R⁶ is heteroaryl, heterocycloalkyl, —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)NR⁸OR⁷,—C(O)R⁸OR⁷, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl), —C(O)(C₆-C₁₄aryl), —C(O)heteroaryl or —C(O)heterocycloalkyl; wherein each groupabove is optionally substituted with one or more substituentsindependently selected from —NR⁷R⁸, —OR⁷, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, wherein each group is optionally substituted with 1 or 2substituents independently selected from —NR⁷R⁸ and —OR⁷;

each of R⁷, R⁸ and R⁹ is independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl,C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀alkyl, heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl portions is optionally substituted with one or moregroups independently selected from hydroxyl, oxo-, halogen, cyano,nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′,—NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′R″,—NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and(heterocycloalkyl)C₁-C₁₀ alkyl;

or

R⁷ and R⁸, together with the atom to which they are attached, form asubstituted or unsubstituted 3- to 10-member ring; wherein each group isoptionally substituted with one or more substituents independentlyselected from halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″,—C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′,—S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′,C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

or

R⁸ and R⁹, together with the atom to which they are attached, form asubstituted or unsubstituted 3- to 10-member ring; wherein each group isoptionally substituted with one or more substituents independentlyselected from H, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″,—C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′,—S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′,C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

R¹⁰ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl,heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl is optionally substituted with one or more groupsindependently selected from oxo-, halogen, cyano, nitro, —CF₃, azido,—NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″,—NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R¹¹, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and(heterocycloalkyl)C₁-C₁₀ alkyl;

R′, R′ and R′″ are independently H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄aryl, or (C₆-C₁₄ aryl)C₁-C₁₀ alkyl;

R″″ is C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄ aryl or (C₆-C₁₄ aryl)C₁-C₁₀alkyl;

or

any two of R′, R″, R′″ and R″″, together with the atom to which they areattached, form a 4- to 10-membered heteroaryl or heterocyclic ring,wherein each heteroaryl and heterocyclic rings is optionally substitutedwith one or more groups independently selected from H, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, C₆-C₁₄ aryl,heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl,heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

X¹ is CR¹¹ or N;

R¹¹ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl,heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl, (C₁-C₁₀alkyl)₃silyl, (C₁-C₁₀ alkyl)₂(C₆-C₁₄ aryl)silyl; wherein each alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl isoptionally substituted with one or more groups independently selectedfrom oxo-, halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″,—C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′,—S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′,C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl (heteroaryl)C₁-C₁₀alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

X² is O, S or —C(═O);

m is 0, 1, 2, 3, 4 or 5; and

j is 0, 1 or 2.

In some embodiments, the compound of the formula (A-I), where X¹ is—CR¹¹, having the formula (A-I-1), or where X¹ is N, having the formula(A-I-2):

In some embodiments, the compound of the formula (A-I) where X¹ is —CR¹¹and X² is O, S, or —C(═O) having the formula (A-I-1-a), (A-I-1-b) or(A-I-1-c) respectively:

In some embodiments, the compound of the formula (A-I) where X¹ is N andX² is O, S, or —C(═O) having the formula (A-I-2-a), (A-I-2-b) or(A-I-2-c) respectively:

Also provided are methods of making compounds of the formula (A-I) andsalts, prodrugs and solvates thereof. For example, a compound of theformula (A-I-1-a), (A-I-1-b), (A-I-2-a) or (A-I-2-b) may be prepared,according to Schemes A-1, A-2, A-3 or A-4 respectively:

wherein R¹, R², R³, R⁴, R⁵ and R¹¹ are as described for the formula(A-I), and

R⁷ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl,heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl is optionally substituted with one or more groupsindependently selected from oxo-, halogen, cyano, nitro, —CF₃, azido,—NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″,—NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R¹¹, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and(heterocycloalkyl)C₁-C₁₀ alkyl;

-   -   R′, R″ and R′″ are independently hydrogen, C₁-C₁₀ alkyl, C₂-C₆        alkenyl, C₆-C₁₄ aryl, or (C₆-C₁₄ aryl)C₁-C₁₀ alkyl;    -   R″″ is C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄ aryl or (C₆-C₁₄        aryl)C₁-C₁₀ alkyl;    -   or    -   any two of R′, R″, R′″ and R″″, together with the atom to which        they are attached, form a 4- to 10-member heteroaryl or        heterocyclic ring, wherein said heteroaryl and heterocyclic        rings are optionally substituted with one or more groups        independently selected from halogen, cyano, nitro,        trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,        C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl,        (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and        (heterocycloalkyl)C₁-C₁₀ alkyl;

each of R¹², R¹³, R¹⁴ and R¹⁵ is independently benzyl, benzylsubstituted with 1 to 3 methoxy, C₁-C₅ alkyl and —SiR¹⁶R¹⁷R¹⁸, whereineach of R¹⁶, R¹⁷ and R¹⁸ is independently selected from C₁-C₁₀ alkyl andC₆-C₁₄ aryl.

In some preferred embodiments, the compound is of the formula (A-I),where X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ are as described as below withvarious degrees of preferences:

Preferred X¹ is CR¹¹ or N;

More preferred X¹ is CR¹¹ or N;

Especially preferred X¹ is CR¹¹ or N;

Particularly preferred X¹ is CR¹¹ or N.

Preferred R¹¹ is H, C₁-C₆ alkyl or (C₃-C₈ cycloalkyl)C₁-C₆ alkyl;

More preferred R¹¹ is H, C₁-C₄ alkyl or (C₃-C₆ cycloalkyl)C₁-C₄ alkyl;

Especially preferred R¹¹ is H or C₁-C₄ alkyl;

Particularly preferred R¹¹ is H.

Preferred R¹, R², R⁴ and R⁵ are each independently H, halogen, C₁-C₁₀alkyl, wherein C₁-C₁₀ alkyl is optionally substituted with one or moresubstituents independently selected from oxo-, halogen, cyano, nitro,—CF₃, azido, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —NR⁸C(O)OR¹⁰, —OC(O)R⁷,—NR⁸SO₂R¹⁶, —SO₂NR⁷R⁸, —NR⁸C(O)R⁷, —C(O)NR⁷R⁸, —NR⁹C(O)NR⁷R⁸,—NR⁹C(NCN)NR⁷R⁸, —NR⁷R⁸, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl,heteroaryl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and(heterocycloalkyl)C₁-C₁₀ alkyl;

More preferred R¹ is H, halogen, C₁-C₆ alkyl, halogenated C₁-C₆ alkyl,halogenated C₁-C₆ alkoxy, or halogenated alkylsulphanyl;

Especially preferred R¹ is H, fluoro, chloro, bromo, C₁-C₄ alkyl,halogenated C₁-C₄ alkyl, halogenated C₁-C₄ alkoxy;

Particularly preferred R¹ is fluorine, chlorine, methyl, —CF₃, —CF₃O.

More preferred R² is H, halogen or C₁-C₆ alkyl;

Especially preferred R² is H, halogen or C₁-C₄ alkyl;

Particularly preferred R² is hydrogen.

More preferred R⁴ is more preferably H;

Especially preferred R⁴ is H;

Particularly preferred R⁴ is H.

More preferred R⁵ is H, halogen or C₁-C₆ alkyl;

Especially preferred R⁵ is H, fluoro, chloro, bromo or C₁-C₄ alkyl;

Particularly preferred R⁵ is H, fluorine, chlorine or methyl.

Preferred R³ is H, halogen, C₁-C₁₀ alkoxy, C₁-C₁₀ alkyl sulphanyl,halogenated C₁-C₁₀ alkoxy, halogenated C₁-C₁₀ alkylsulphanyl orhalogenated C₁-C₁₀ alkyl;

More preferred R³ is fluoro, chloro, bromo, iodo, C₁-C₆ alkoxy, C₁-C₆alkyl sulphanyl, halogenated C₁-C₆ alkoxy, halogenated C₁-C₆alkylsulphanyl or halogenated C₁-C₆ alkyl;

Especially preferred R³ is bromo, iodo, C₁-C₄ alkylsulphanyl,halogenated C₁-C₄ alkoxy, or halogenated C₁-C₄ alkyl;

Particularly preferred R³ is bromo, iodo, —SCH₃, —OCF₃, —CF₃.

Preferred R⁶ is —C(O)NR⁸OR⁷ or —C(O)NR⁸R⁷;

each of R⁷, R⁸ and R⁹ is independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl,C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀alkyl, heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl is optionally substituted with one or more groupsindependently selected from hydroxyl, oxo-, halogen, cyano, nitro, —CF₃,azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″,—NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and(heterocycloalkyl)C₁-C₁₀ alkyl;

or

R⁷ and R⁸, together with the atom to which they are attached, form asubstituted or unsubstituted 3- to 10-member ring; wherein each group isoptionally substituted with one or more substituents independentlyselected from halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″,—C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′,—S(O)R″″, —SO₂R″″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl,heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl,heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

or

R⁸ and R⁹, together with the atom to which they are attached, form asubstituted or unsubstituted 3- to 10-member ring; wherein each group isoptionally substituted with one or more substituents independentlyselected from halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″″, —SO₂NR′R″,—C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′,—S(O)R″″, —SO₂R″″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl,heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl,heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

R¹⁰ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl,heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl is optionally substituted with one or more groupsindependently selected from oxo-, halogen, cyano, nitro, —CF₃, azido,—NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″,—NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R¹¹, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and(heterocycloalkyl)C₁-C₁₀ alkyl;

R′, R″ and R′″ are independently hydrogen, C₁-C₁₀ alkyl, C₂-C₆ alkenyl,C₆-C₁₄ aryl, or (C₆-C₁₄ aryl)C₁-C₁₀ alkyl;

R″″ is C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄ aryl or (C₆-C₁₄ aryl)C₁-C₁₀alkyl;

or

any two of R′, R″, R′″ and R″″, together with the atom to which they areattached, form a 4- to 10-member heteroaryl or heterocyclic ring,wherein each of heteroaryl and heterocyclic rings is optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl.

More preferred R⁶ is —C(O)NR⁸OR⁷ or —C(O)NR⁸R⁷;

More preferred R⁷ is C₁-C₆ alkyl substituted with 1 to 6 hydroxy groups,or (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl;

More preferred R⁸ is hydrogen or C₁-C₆ alkyl.

Especially preferred R⁶ is —C(O)NR⁸OR⁷ or —C(O)NR⁸R⁷;

Especially preferred R⁷ is C₁-C₄ alkyl substituted with 1 to 3 hydroxygroups, or (C₃-C₈ cycloalkyl)C₁-C₆ alkyl;

Especially preferred R⁸ is hydrogen or C₁-C₄ alkyl.

Particularly preferred R⁶ is —C(O)NHOR⁷ or —C(O)NHR⁷.

Particularly preferred R⁷ is ethyl, propyl or isobutyl substituted with1 to 3 hydroxy groups, or (C₃-C₆ cycloalkyl) C₁-C₄ alkyl.

In some preferred embodiments, the compound is of the formula (A-I),where X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ are as defined for the preferredvariations for the X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ groups describedabove.

In some more preferred embodiments, the compound is of the formula(A-I), where X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ are as defined for themore preferred variations for the X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶groups described above.

In some especially preferred embodiments, the compound is of the formula(A-I), where X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ are as defined for theespecially preferred variations for the X¹, X², R¹, R², R³, R⁴, R⁵ andR⁶ groups described above.

In some particularly preferred embodiments, the compound is of theformula (A-I), where X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ are as definedfor the particularly preferred variations for the X¹, X², R¹, R², R³,R⁴, R⁵ and R⁶ groups described above.

It is intended and understood that each and every variations of the X¹,X², R¹, R², R³, R⁴, R⁵ and R⁶ groups of the compound of the formula(A-I) may be combined, that is, the non-preferred variations andvariations with different degrees of preferences as specified above forthe formula (A-I) may be combined. Such combinations are applicable tothe synthetic precursors and intermediates as they are applied to thefinal product in the synthetic methods and schemes, for example, inSchemes A-1, A-2, A-3 and A-4.

Saturated or unsaturated hydrocarbon radicals (e.g., C₁-C₁₀ alkyl,alkylene or alkenyl), as well as when they are attached a heteroatom(e.g., alkoxy) may be a linear or branched chain.

Unless otherwise specified, any groups may be optionally substitutedwith a single substituent or with multiple substituents, and thesubstituents in a multiply substituted group may be the same ordifferent.

In some embodiments, provided is a compound of the formula (A-I-1-a-1),(A-I-1-b-1), (A-I-1-c-1), (A-I-2-a-1), (A-I-2-b-1) or (A-I-2-c-1):

or a salt, prodrug or solvate thereof, wherein the —C(O)NHOR⁷ moiety isselected from the group consisting of:

and R¹, R³ and R⁵ are as described in Table 4.

TABLE 4 R¹ R³ R⁵ R¹ R³ R⁵ R¹ R³ R⁵ F Br F F Br Me F Br H F I F F I Me FI H F SMe F F SMe Me F SMe H F OCF₃ F F OCF₃ Me F OCF₃ H Cl Br F Cl BrMe Cl Br H Cl I F Cl I Me Cl I H Cl SMe F Cl SMe Me Cl SMe H Cl OCF₃ FCl OCF₃ Me Cl OCF₃ H Me Br F Me Br Me Me Br H Me I F Me I Me Me I H MeSMe F Me SMe Me Me SMe H Me OCF₃ F Me OCF₃ Me Me OCF₃ H

Synthesis

Compounds of the formula (A-I) or any variations thereof may besynthesized following synthetic routes illustrated in Schemes (A-1-1),(A-2-1), (A-3-1) and (A-4-1).

The synthetic route according to Scheme A-1-1 is further illustrated bya synthetic process for4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamideas outline in Scheme A-1-1-1 and the following steps.

Step 1:

2,3,4-Trifluorophenol was protected with hydroxy protection reagent(examples include BnBr, BnCl) at ambient temperature in the presence ofbase (include Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, t-BuOK, t-BuONa) inappropriate inert solvent (include aliphatic and aromatic hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol,gasoline, benzene, toluene, xylene), aliphatic and aromatichalo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane,chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether(such asdiethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethylether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethylketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such asethyl acetate, methyl acetate), nitrile (such as acetonitrile,propiononitrile), amide (such as N,N-dimethylformamide,N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane,HMPA, DMPU, prefer acetone and methyl ethyl ketone). The reactionproceeds for several hours (3-12 h, prefer 5-10 h).1-(Benzyloxy)-2,3,4-trifluorobenzene is obtained after conventionalworkup.

Step 2:

To a solution of 1-benzyloxy-2,3,4-trifluorobenzene in appropriate inertsolvent (such as, but not limited to, aliphatic and aromatic hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol,gasoline, benzene, toluene, xylene), ether (such as diethyl ether,dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether,tetrahydrofuran, dioxane), sulfolane, HMPA, DMPU, prefer anhydrous THF,ethyl ether and dioxane) was added strong base (such as LDA, n-BuLi,LiHDMS) at low temperature (−50-−80° C., prefer −78° C.) under nitrogenatmosphere. The stirring was maintained at this temperature for severalhours (such as 0.5-12 h, prefer 0.5-2 h). The mixture was transferred toa bottle with dry ice. The mixture is stirred for some time (such as3-12 h, prefer 5-10 h). 5-Benzoxy-2,3,4-trifluorobenzoic acid isobtained after conventional workup.

Step 3:

5-Benzoxy-2,3,4-trifluorobenzoic acid can be reacted with halogenatedaniline (such as o-fluoroaniline, o-chloroaniline, o-bromoaniline,o-iodoaniline) under strong basic condition (such as LDA, n-BuLi,LiHDMS) at low temperature (−50-−80° C., prefer −78° C.) for some time(such as 3-12 h, prefer 5-10 h).5-(Benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid isobtained after conventional workup.

Step 4:

5-(Benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can beprotected by acid or hydroxyl protection reagent (such as BnBr, BnCl) atambient temperature in the presence of base (includes Na₂CO₃, K₂CO₃,NaHCO₃, KHCO₃, t-BuOK, t-BuONa) in appropriate inert solvent (includealiphatic and aromatic hydrocarbon (such as pentane, hexane, heptane,cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene,xylene), aliphatic and aromatic halo-hydrocarbon (such asdichloromethane, 1,2-dichloroethane, chloroform, phenixin,chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutylether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran,dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropylketone, methyl isobutyl ketone), ester (such as ethyl acetate, methylacetate), nitrile (such as acetonitrile, propiononitrile), amide (suchas N,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer acetoneand methyl ethyl ketone). The reaction proceeds for several hours (3-12h, prefer 5-10 h). Benzyl5-(benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtainedafter conventional workup.

Step 5:

Benzyl 5-(benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate canbe reacted with azide (such as NaN₃, KN₃) in appropriate solvent(include aliphatic and aromatic hydrocarbon (such as pentane, hexane,heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene,toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such asdichloromethane, 1,2-dichloroethane, chloroform, phenixin,chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutylether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran,dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropylketone, methyl isobutyl ketone), ester (such as ethyl acetate, methylacetate), nitrile (such as acetonitrile, propiononitrile), amide (suchas N,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, preferN,N-dimethylformamide and N,N-dimethylacetamide) for some time (1-12 h,prefer 3-10 h). Benzyl4-azido-5-(benzyloxy)-3-fluoro-2-((2-fluorophenyl)amino)benzoate isobtained after conventional workup.

Step 6:

Benzyl 4-azido-5-(benzyloxy)-3-fluoro-2-((2-fluorophenyl)amino)benzoatecan be hydrogenated catalyzed by appropriate catalyst (such as Pd/C, Pt,Ni) in the solvent (include aliphatic and aromatic hydrocarbon (such aspentane, hexane, heptane, cyclohexane, petroleum ether, petrol,gasoline, benzene, toluene, xylene), ether (such as diethyl ether,dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether,tetrahydrofuran, dioxane), ester (such as ethyl acetate, methylacetate), amide (such as N,N-dimethylformamide, N,N-dimethylacetamideand N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefermethanol, ethanol, propan-1-ol and water) for some time (1-12 h, prefer3-10 h). 4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoicacid is obtained after conventional workup.

Step 7:

4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid can becyclized in the presence of acid (such as p-toluenesulfonic acid,pyridinium toluene-4-sulphonate, formic acid, acetic acid, sulfuricacid) in appropriate solvent (include aliphatic and aromatic hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol,gasoline, benzene, toluene, xylene), aliphatic and aromatichalo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane,chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such asdiethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethylether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethylketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such asethyl acetate, methyl acetate), nitrile (such as acetonitrile,propiononitrile), amide (such as N,N-dimethylformamide,N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane,HMPA, DMPU, prefer methyl acetate, ethyl acetate and trimethoxymethane)for some time (0.2-12 h, prefer 0.5-10 h).4-Fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid isobtained after conventional workup.

Step 8:

4-Fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid canbe reacted with halogenations reagent (such as NIS) in the presence ofacid (such as trifluoroacetic acid, trifluoromethanesulfonic acid,methanesulfonic acid, formic acid, acetic acid) at ambient temperaturein appropriate solvent (include aliphatic and aromatic hydrocarbon (suchas pentane, hexane, heptane, cyclohexane, petroleum ether, petrol,gasoline, benzene, toluene, xylene), aliphatic and aromatichalo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane,chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such asdiethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethylether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethylketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such asethyl acetate, methyl acetate), nitrile (such as acetonitrile,propiononitrile), amide (such as N,N-dimethylformamide,N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane,HMPA, DMPU, prefer N,N-dimethylformamide and N,N-dimethylacetamide) forsome time (1-12 h, prefer 3-10 h).4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylicacid is obtained after conventional workup.

Step 9:

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxyl canbe reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence ofcoupling reagent (such as HOBt, EDCI, HATU, TBTU) at ambient temperaturein appropriate solvent (include aliphatic and aromatic hydrocarbon (suchas pentane, hexane, heptane, cyclohexane, petroleum ether, petrol,gasoline, benzene, toluene, xylene), aliphatic and aromatichalo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane,chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such asdiethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethylether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethylketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such asethyl acetate, methyl acetate), nitrile (such as acetonitrile,propiononitrile), amide (such as N,N-dimethylformamide,N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane,HMPA, DMPU, prefer dichloromethane, 1,2-dichloroethane andN,N-dimethylformamide) for some time (1-12 h, prefer 3-10 h).4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamideis obtained after conventional workup.

Step 10:

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamidecan be reacted in the presence of acid (such as hydrochloric acid,sulfuric acid, trifluoroacetic acid) in appropriate solvent (includealiphatic and aromatic hydrocarbon (such as pentane, hexane, heptane,cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene,xylene), aliphatic and aromatic halo-hydrocarbon (such asdichloromethane, 1,2-dichloroethane, chloroform, phenixin,chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutylether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran,dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropylketone, methyl isobutyl ketone), ester (such as ethyl acetate, methylacetate), nitrile (such as acetonitrile, propiononitrile), amide (suchas N,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA DMPU, preferdichloromethane and 1,2-dichloroethane) for some time (1-12 h, prefer3-10 h).4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)beno[d]oxazole-6-carboxamideis obtained after conventional workup.

The synthetic route according to Scheme A-2-1 is further illustrated bya synthetic process for4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamideas outline in Scheme A-2-1-1 and the following steps.

Step 1:

To a solution of 2,3,4-trifluorobromobenzene in appropriate solvent(include aliphatic and aromatic hydrocarbon (such as pentane, hexane,heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene,toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycoldimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane),sulfolane, HMPA, DMPU, prefer anhydrous THF, ethyl ether and dioxane)was added strong base (such as LDA, nBuLi, LiHDMS) at low temperature(−50-−80° C., prefer −78° C.) under nitrogen atmosphere. The reaction iskept stirring for some time (0.5-12 h, prefer 0.5-2 h) and is added dryice. After several hours (3-12 h, prefer 5-10 h),5-bromo-2,3,4-trifluorobenzoic acid is obtained after conventionalworkup.

Step 2:

5-Bromo-2,3,4-trifluorobenzoic acid can be reacted with halogenatedaniline (such as o-fluoroaniline, o-chloroaniline, o-bromoaniline,o-iodoaniline) in the presence of base (such as LDA, n-BuLi, LiHDMS) inappropriate solvent (include aliphatic and aromatic hydrocarbon (such aspentane, hexane, heptane, cyclohexane, petroleum ether, petrol,gasoline, benzene, toluene, xylene), ether (such as diethyl ether,dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether,tetrahydrofuran, dioxane), sulfolane, HMPA, DMPU, prefer anhydrous THF,ethyl ether and dioxane) at low temperature (−50-−80° C., prefer −78°C.) for some time (such as 3-12 h, prefer 5-10 h).5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid is obtainedafter conventional workup.

Step 3:

5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can bereacted with MeOH in the presence of SOCl₂ in appropriate solvent(include aliphatic and aromatic hydrocarbon (such as pentane, hexane,heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene,toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such asdichloromethane, 1,2-dichloroethane, chloroform, phenixin,chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutylether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran,dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropylketone, methyl isobutyl ketone), ester (such as ethyl acetate, methylacetate), nitrile (such as acetonitrile, propiononitrile), amide (suchas N,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methanoland ethanol). The reaction proceeds for several hours (3-12 h, prefer5-10 h). Methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoateis obtained after conventional workup.

Step 4:

To a solution of methyl5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate in appropriatesolvent (include aliphatic and aromatic hydrocarbon (such as pentane,hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline,benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether,glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane),ester (such as ethyl acetate, methyl acetate), nitrile (such asacetonitrile, propiononitrile), amide (such as N,N-dimethylformamide,N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane,HMPA, DMPU, prefer dioxane) was added base (such as aliphatic andaromatic amine (such as, but not limited to,N-ethyl-N-isopropylpropan-2-amine, triethylamine, diethylamine, DBU,t-butylamine, cyclopropanamine, dibutylamine, diisopropylamine,1,2-dimethylpropanamine), inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃,KHCO₃, t-BuONa, t-BuOK), prefer N-ethyl-N-isopropylpropan-2-amine) atambient temperature under nitrogen atmosphere, followed by Pd catalyst(such as tris(dibenzylideneacetone)dipalladium,bis(dibenzylideneacetone) palladium,bis(triphenylphosphine)palladium(II) chloride, palladium diacetate,tetrakis(triphenylphosphine)palladium,bis(triphenylphosphinepalladium)acetate, prefertris(dibenzylideneacetone)dipalladium) and phosphine ligand (such asdimethylbisdiphenylphosphinoxanthene, tri-tert-butylphosphine,tri-p-tolylphosphine, tris(4-chlorophenyl)phosphine,triisopropylphosphine, tris(2,6-dimethoxyphenyl)phosphine,1,1′-bis(diphenylphosphino)ferrocene, preferdimethylbisdiphenylphosphinoxanthene). The reaction is kept stirring athigh temperature (80-130° C., prefer 90-110° C.) for some time (8-24 h,prefer 12-18 h). Methyl3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoateis obtained after conventional workup.

Step 5:

Methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate can be reacted with azide (such as NaN₃, KN₃) athigh temperature (60-120° C., prefer 80-100° C.) in appropriate solvent(include aliphatic and aromatic hydrocarbon (such as pentane, hexane,heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene,toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such asdichloromethane, 1,2-dichloroethane, chloroform, phenixin,chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutylether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran,dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropylketone, methyl isobutyl ketone), ester (such as ethyl acetate, methylacetate), nitrile (such as acetonitrile, propiononitrile), amide (suchas N,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, preferN,N-dimethylformamide and N,N-dimethylacetamide) for some time (1-12 h,prefer 3-10 h). Methyl4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoateis obtained after conventional workup.

Step 6:

Methyl 4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate can be hydrogenated catalyzed by appropriatecatalyst (such as Pd/C, Pt, Ni) in the solvent (include aliphatic andaromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane,petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether(such as diethyl ether, dibutyl ether, glycol dimethyl ether,2-methoxyethyl ether, tetrahydrofuran, dioxane), ester (such as ethylacetate, methyl acetate), amide (such as N,N-dimethylformamide,N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane,HMPA, DMPU, prefer methanol, ethanol, propan-1-ol and water) for sometime (1-12 h, prefer 3-10 h). Methyl4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoateis obtained after conventional workup.

Step 7:

4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoatecan be deprotected in the presence of acid (such as CF₃COOH, HCOOH,CH₃COOH and n-C₅H₁₁COOH, prefer CF₃COOH) at certain temperature (20-75°C., prefer 25-75° C.) in appropriate aromatic aliphatic ether (such asanisole and phenetole, prefer anisole) for some time (1-12 h, prefer3-10 h). Methyl4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate isobtained after conventional workup.

Step 8:

Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercapto benzoatecan be cyclized in the presence of acid (such as p-toluenesulfonic acid,pyridinium toluene-4-sulphonate, formic acid, acetic acid, sulfuricacid) in appropriate solvent (include aliphatic and aromatic hydrocarbon(such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol,gasoline, benzene, toluene, xylene), aliphatic and aromatichalo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane,chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such asdiethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethylether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethylketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such asethyl acetate, methyl acetate), nitrile (such as acetonitrile,propiononitrile), amide (such as N,N-dimethylformamide,N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane,HMPA, DMPU, prefer methyl acetate, ethyl acetate and trimethoxymethane)for some time (0.2-12 h, prefer 0.5-10 h). Methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate isobtained after conventional workup.

Step 9:

Methyl 4-fluoro-5((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylatecan be reacted with halogenations reagent (such as NIS) in the presenceof acid (such as trifluoroacetic acid, trifluoromethanesulfonic acid,methanesulfonic acid, formic acid, acetic acid) at ambient temperaturein appropriate solvent (include aliphatic and aromatic hydrocarbon (suchas pentane, hexane, heptane, cyclohexane, petroleum ether, petrol,gasoline, benzene, toluene, xylene), aliphatic and aromatichalo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane,chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such asdiethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethylether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethylketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such asethyl acetate, methyl acetate), nitrile (such as acetonitrile,propiononitrile), amide (such as N,N-dimethylformamide,N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane,HMPA, DMPU, prefer N,N-dimethylformamide and N,N-dimethylacetamide) forsome time (1-12 h, prefer 3-10 h). Methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylateis obtained after conventional workup.

Step 10:

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylicacid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in thepresence of coupling reagent (such as HOBt, EDCI, HATU, TBTU) at ambienttemperature in appropriate solvent (include aliphatic and aromatichydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleumether, petrol, gasoline, benzene, toluene, xylene), aliphatic andaromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane,chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such asdiethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethylether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethylketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such asethyl acetate, methyl acetate), nitrile (such as acetonitrile,propiononitrile), amide (such as N,N-dimethylformamide,N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane,HMPA, DMPU, prefer dichloromethane, 1,2-dichloroethane andN,N-dimethylformamide) for some time (1-12 h, prefer 3-10 h).4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamideis obtained after conventional workup.

Step 11:

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamidecan be reacted in the presence of acid (such as HCl, H₂SO₄,trifluoroacetic acid) in appropriate solvent (include aliphatic andaromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane,petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphaticand aromatic halo-hydrocarbon (such as dichloromethane,1,2-dichloroethane, chloroform, phenixin, chlorobenzene,o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycoldimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone(such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methylisobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile(such as acetonitrile, propiononitrile), amide (such asN,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, preferdichloromethane and 1,2-dichloroethane) for some time (1-12 h, prefer3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide is obtained after conventionalworkup.

The synthetic route according to Scheme A-3-1 is further illustrated bya synthetic route for4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]oxadiazole-6-carboxamideas outline in Scheme A-3-1-1.

The synthetic route according to Scheme A-1-1 is further illustrated bya synthetic process for4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N42-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamideas outline in Scheme A-4-1-1.

In the synthetic processes described in Schemes (A-1-1), (A-2-1),(A-3-1) and (A-4-1), R¹, R², R³, R⁴, R⁵ and R¹¹ are as defined for theformula (A-I) or any variations thereof, such as the preferredvariations, the more preferred variations, the especially preferredvariations and the particularly preferred variations of R¹, R², R³, R⁴,R⁵ and R¹¹ as describe here above, or any combinations thereof;

Preferred R⁷ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl,heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl andheterocycloalkyl is optionally substituted with one or more groupsindependently selected from hydroxyl, oxo-, halogen, cyano, nitro, —CF₃,azido, —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″,—NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R¹¹, —NR′R″, —NR′C(O)NR″R′″,—NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and(heterocycloalkyl)C₁-C₁₀ alkyl;

R′, R″ and R′″ are independently H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄aryl, or (C₆-C₁₄ aryl)C₁-C₁₀ alkyl;

R″″ is C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄ aryl or (C₆-C₁₄ aryl) C₁-C₁₀alkyl;

or any two of R′, R″, R′″ and R″″, together with the atom to which theyare attached, form a 4- to 10-member heteroaryl or heterocyclic ring,wherein said heteroaryl and heterocyclic rings are optionallysubstituted with one or more groups independently selected from halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

More preferred R⁷ is C₁-C₆ alkyl optionally substituted with 1 to 6hydroxy groups, or (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl;

Especially preferred R⁷ is C₁-C₄ alkyl optionally substituted with 1 to3 hydroxy groups, or (C₃-C₈ cycloalkyl)C₁-C₆ alkyl;

Particularly preferred R⁷ is ethyl, propyl or isobutyl which areoptionally substituted with 1 to 3 hydroxy groups, or (C₃-C₆cycloalkyl)C₁-C₄ alkyl.

Preferred R¹², R¹³, R¹⁴ and R¹⁵ are independently benzyl, benzylsubstituted with 1 to 3 methoxy, C₁-C₄ alkyl, or —SiR¹⁶R¹⁷R¹⁸, whereinR¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄aryl;

More preferred R¹², R¹³, R¹⁴ and R¹⁵ are independently benzyl, benzylsubstituted with 1 to 2 methoxy, C₁-C₄ alkyl, tert-butyldimethylsilyl,triphenylsilyl, trimethylsilyl, triethylsilyl, tripropylsilyl ortriisopropylsilyl;

Especially preferred R¹², R¹³, R¹⁴ and R¹⁵ are independently benzyl,o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl or C₁-C₂ alkyl;Particularly preferred R¹², R¹³, R¹⁴ and R¹⁵ are independently benzyl,p-methoxybenzyl or methyl.

Pharmaceutical Compositions

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions according to theinvention may take a form suitable for oral, buccal, parenteral, nasal,topical or rectal administration or a form suitable for administrationby inhalation.

The present invention embraces the free base of compounds detailedherein, such as a compound of the formula (I), (J), (K), (A-I) or anyvariations thereof, as well as the pharmaceutically acceptable salts andstereoisomers thereof. The compounds of the present invention can beprotonated at the N atom(s) of an amine and/or N containing heterocyclemoiety to form a salt. The term “free base” refers to the aminecompounds in non-salt form. The encompassed pharmaceutically acceptablesalts not only include the salts exemplified for the specific compoundsdescribed herein, but also all the typical pharmaceutically acceptablesalts of the free form of compounds detailed herein, such as a compoundof the formula (I), (J), (K), (A-I) or any variations thereof. The freeform of the specific salt compounds described may be isolated usingtechniques known in the art. For example, the free form may beregenerated by treating a salt with a suitable dilute aqueous basesolution such as dilute aqueous NaOH, potassium carbonate, ammonia andsodium bicarbonate. The free base forms may differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the acid and base salts are otherwisepharmaceutically equivalent to their respective free forms for purposesof the invention.

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

The invention also provides pharmaceutical compositions comprising oneor more compounds detailed herein, such as a compound of the formula(I), (J), (K), (A-I) or any variations thereof, and a pharmaceuticallyacceptable carrier. The pharmaceutical compositions containing theactive ingredient may be in a form suitable for oral use, for example,as tablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be, for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example,microcrystalline cellulose, sodium crosscarmellose, corn starch, oralginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to mask the unpleasant taste ofthe drug or delay disintegration and absorption in the gastrointestinaltract and thereby provide a sustained action over a longer period. Forexample, a water soluble taste masking material such ashydroxypropylmethylcellulose or hydroxypropylcellulose, or a time delaymaterial such as ethyl cellulose, cellulose acetate butyrate may beemployed.

Medical Uses

Benzoheterocyclic compounds of the invention, such as such asbenzothiadiazole, benzoxazole and benzothiazole derivatives detailedherein, are inhibitors of protein kinases such as MEK. The compounds maybe useful in the treatment of conditions or disorders where the MEKcascade is implicated such as cancer and inflammatory diseases.

The invention provides compounds for use in the treatment or preventionof diseases or conditions which can be ameliorated by the inhibition ofMEK. Thus, the present invention provides a compound, such as a compoundof the formula (I), (J), (K), (A-I) or any variations thereof, for usein the manufacture of a medicament for the treatment or prevention ofdiseases or conditions which can be ameliorated by the inhibition ofMEK, such as cancer, acute and chronic inflammatory disease, a skindisease, diabetes, an eye disease, vasculogenesis, angiogenesis, orchronic pain.

In some embodiments, the disease or conditions treatable may includetumor (non-limiting examples include: hemangioma, glioma, melanoma,Kaposi's sarcoma, ovarian cancer, breast cancer, lung cancer, pancreaticcancer, prostate cancer, colon cancer, colorectal cancer andgastrointestinal cancer), chronic inflammatory disease (non-limitingexamples include: rheumatoid arthritis), disease related tovasculogenesis or angiogenesis of mammals, atherosclerosis, inflammatorybowel disease, dermatopathya (non-limiting examples include: psoriasis,excema and scleroderma), diabetes mellitus, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration, diseasesrelated to chronic pain (including neuralgia and pain arising from otherdiseases related to MEK; non-limiting examples include: phantom limbpain, burn pain, gout, trigeminal neuralgia, acute herpetic,postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion,neuroma, vasculitis, crush injury, constriction injury, tissue injury,post-surgical pain, arthritis pain and limb amputation).

Also provided is a method for the treatment or prevention of a diseaseor condition mediated by MEK, said method comprises administering to anindividual in need thereof a therapeutically effective amount of acompound detailed herein, such as a compound of the formula (I), (J),(K), (A-I) or any variations thereof, or a composition comprising acompound detailed herein, such as a compound of the formula (I), (J),(K), (A-I) or any variations thereof. In some embodiments, the diseaseor condition mediated by MEK is cancer, chronic inflammatory disease, askin disease, diabetes, an eye disease, vasculogenesis, angiogenesis orchronic pain.

In some embodiments, the invention provides a method for the treatmentor prevention of cancer, comprising administration to an individual inneed thereof of an effective amount of a compound detailed herein, suchas a compound of the formula (I), (J), (K), (A-I) or any variationsthereof, or a composition comprising a compound detailed herein, such asa compound of the formula (I), (J), (K), (A-I) or any variationsthereof. In some embodiments, the cancer is a cancer detailed below. Insome embodiments, the cancer is colon cancer, colorectal cancer, lungcancer (e.g., non-small cell lung cancer), pancreatic cancer, breastcancer, ovarian cancer, prostate cancer or skin cancer (e.g. melanoma).

In some embodiments, the invention provides a method for the treatmentor prevention of inflammatory diseases, comprising administration to anindividual in need thereof of an effective amount of a compound detailedherein, such as a compound of the formula (I), (J), (K), (A-I) or anyvariations thereof or a composition comprising a compound detailedherein, such as a compound of the formula (I), (J), (K), (A-I) or anyvariations thereof. In some embodiment, the inflammatory disease is therheumatoid arthritis or inflammatory bowel disease.

The compounds of the invention are useful for the treatment ofinflammatory diseases, including conditions resulting from organtransplant rejection; chronic inflammatory diseases of the joints,including arthritis, rheumatoid arthritis; inflammatory bowel diseasessuch as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn'sdisease; inflammatory lung diseases such as asthma, adult respiratorydistress syndrome, and chronic obstructive airway disease; inflammatorydiseases of the eye; chronic inflammatory diseases of the gum;inflammatory diseases of the kidney; inflammatory diseases of the skin;inflammatory diseases of the central nervous system; inflammatorydiseases of the heart such as cardiomyopathy, ischemic heart disease,and atherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma.

The present invention also provides a compound, such as a compound ofthe formula (I), (J), (K), (A-I) or any variations thereof, for use inthe manufacture of a medicament for treating or preventing inflammatorydiseases.

In some embodiments, the invention provides a method for the treatmentchronic pain, comprising administration to an individual in need thereofof an effective amount of a compound detailed herein, such as a compoundof the formula (I), (J), (K), (A-I) or any variations thereof or acomposition comprising a compound detailed herein, such as a compound ofthe formula (I), (J), (K), (A-I) or any variations thereof. In someembodiment, the chronic pain is phantom limb pain, burn pain, gout,trigeminal neuralgia, acute herpetic pain, postherpetic pain, causalgia,diabetic neuropathy, plexus avulsion, neuroma, vasculitis, crush injury,constriction injury, tissue injury, post-surgical pain, arthritis painand limb amputation.

The compounds of this invention, such as a compound of the formula (I),(J), (K), (A-I) or any variations thereof, may be administered tomammals, preferably humans, either alone or in combination withpharmaceutically acceptable carriers, excipients, diluents, adjuvants,fillers, buffers, stabilizers, preservatives, lubricants, in apharmaceutical composition, according to standard pharmaceuticalpractice.

Administration in vivo can be effected in one dose, continuously orintermittently (e.g. in divided doses at appropriate intervals)throughout the course of treatment. Methods of determining the mosteffective means and dosage of administration are well known to those ofskill in the art and will vary with the formulation used for therapy,the purpose of the therapy, the target cell being treated, and thesubject being treated. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician. Where the active compound is a salt, an ester, prodrug, orthe like, the amount administered is calculated on the basis of theparent compound and so the actual weight to be used is increasedproportionately. As a skilled artisan would understand, the dosage maybe determined using known methods, and taking into consideration theage, body weight and health of the individual in need, the type ofcondition treated and presence of other drugs available. In someembodiments, the effective dose is about 0.1 to about 1000 mg/kg bodyweight. In some embodiment, the effective dose is about 1 to about 300mg/kg body weight. For an average adult, a daily dose may be about 10 to2500 mg, about 100 mg, about 200 mg, about 300 mg or about 400 mg.

The compounds of this invention may be administered to an individual byany convenient route of administration, whethersystemically/peripherally or at the site of desired action, includingbut not limited to, oral (e.g. by ingestion); topical (including e.g.transdermal, intranasal, ocular, buccal, and sublingual); pulmonary(e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g.through mouth or nose); rectal; vaginal; parenteral, (e.g. by injection,including subcutaneous, intradermal, intramuscular, intravenous,intraarterial, intracardiac, intrathecal, intraspinal, intracapsular,subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular,intraarticular, subarachnoid, and intrasternal); and by implant of adepot (e.g. subcutaneously or intramuscularly). The individual may be ananimal or a human.

The compounds may be administered in any suitable dosage forms such assolution, emulsion, water and oil suspension, powder, paste, solublepowder, granules, suspension emulsion thickener, capsule, tablet,potion, draught, pills, suppositories, and other suitable forms.

In some embodiments, the method of treating a disease on conditionmediated by MEK, such as cancer, further comprises one or moreadditional active agent used in combination with a compound of theinvention.

EXAMPLES

Compounds detailed herein may be prepared by those of skill in the artby referral to the General Method. Particular examples of the GeneralMethod are provided in the Examples below. The following Examples areprovided to illustrate but not to limit the invention.

Example 1 Preparation of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide(Compound 1)

Step 1: 1-benzyloxy-2,3,4-trifluorobenzene

Sodium carbonate (19.50 g, 183.96 mmol) was dispersed into a solution of2,3,4-trifluorophenol (13.64 g, 92.10 mmol) in acetone (300 mL). To thestirred suspension was added benzyl bromide (17.31 g, 101.21 mmol)dropwisely. The mixture was heated under reflux at 50° C. for 24 h. Theacetone was removed under reduced pressure and the residue was dissolvedin water (300 mL). The solution was extracted with ethyl acetate (100mL×2). The combined organic extracts were washed with 5% sodiumhydroxide (100 mL) and brine (100 mL) sequentially and dried overNa₂SO₄. The solvent was removed in vacuo to yield a pale yellow solid(19.89 g, 90.7% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.40 (m, 5H), 6.85(m, 1H), 6.64 (m, 1H), 5.15 (s, 2H).

Step 2: 5-benzyloxy-2,3,4-trifluorobenzoic acid

To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL)was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C.under nitrogen atmosphere. The stirring was maintained at thistemperature for 1 h. Then a solution of1-benzyloxy-2,3,4-trifluorobenzene (19.89 g, 83.50 mmol) in THF (120 mL)was added. After stirring for 1 h at −78° C., the mixture wastransferred to a bottle with dry ice. The mixture was stirred overnightat room temperature. The reaction was quenched with 10% aqueous HCl andpH was adjusted to 1-2. The mixture was extracted with ethyl acetate(100 mL×3). The combined organic extracts were washed with water (100mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the desired product (whitesolid, 19.33 g, 82% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.42 (m, 6H),5.14 (s, 2H).

Step 3: 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (15.23 g, 137 mmol) and5-benzyl-oxy-2,3,4-trifluorobenzoic acid (19.33 g, 68.50 mmol) in THF(120 mL) at −78° C. was added LiHMDS (205.5 mL, 1 M in THF, 205.50 mmol)dropwisely. The mixture was allowed to slowly warm to room temperatureand stirred at this temperature overnight. The reaction was quenchedwith water (100 mL) and acidified to pH 2-3 with 10% HCl (aq.). Theaqueous layer was extracted with ethyl acetate (100 mL×3). The combinedorganic extracts were washed with water (100 mL) and brine (100 mL)sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo toafford the desired product (pale yellow solid, 19.17 g, 75% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 13.76 (s, 1H), 8.58 (s, 1H), 7.61 (dd, J=8.8,1.7 Hz, 1H), 7.44 (m, 5H), 7.20 (m, 1H), 7.05 (m, 1H), 6.90 (m, 2H),5.26 (s, 2H).

Step 4: benzyl5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (19.17 g,51.35 mmol) in DMF (150 mL) was added potassium bicarbonate (6.16 g,61.62 mmol) followed by benzyl bromide (6.2 mL, 51.41 mmol). The mixturewas stirred for 5 h at room temperature and water was added. Thesolution was extracted with ethyl acetate (100 mL×3). The combinedorganic extracts were washed with water (100 mL) and brine (100 mL)sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo.After purification by column chromatography on silica gel (petroleumether/ethyl acetate, 50:1, v/v), the corresponding product was obtainedas white solid (21.42 g, 90% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.51 (s,1H), 7.51 (dd, J=8.5, 2.1 Hz, 1H), 7.41 (m, 10H), 7.09 (m, 1H), 7.03 (m,1H), 6.94 (m, 1H), 6.85 (m, 1H), 5.33 (s, 2H), 5.15 (s, 2H).

Step 5: benzyl4-azido-5-benzyloxy-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of benzyl5-benzyloxy-3,4-difluoro-2-((2-fluoro-phenyl)amino)benzoate (21.42 g,46.22 mmol) in DMF (150 mL) was added NaN₃ (3.61 g, 55.46 mmol). Themixture was stirred at 90° C. for 3 h. Then water (300 mL) was added.The solution was extracted with ethyl acetate (100 mL×3). The combinedorganic extracts were washed with water (100 mL) and brine (100 mL),dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (petroleum ether/ethylacetate, 50:1, v/v) and gave the desired product (pale yellow solid,14.63 g, 65% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.45 (s, 1H), 7.49 (s,1H), 7.39 (m, 10H), 7.07 (m, 1H), 7.04 (m, 1H), 6.90 (m, 1H), 6.83 (m,1H), 5.31 (s, 2H), 5.13 (s, 2H).

Step 6: 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxy benzoicacid

To a solution of benzyl4-azido-5-benzyloxy-3-fluoro-2-((2-fluoro-phenyl)amino)benzoate (14.63g, 30.07 mmol) in MeOH (200 mL) was added and 10% palladium on carbon(2.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere wascompletely changed to hydrogen atmosphere. The mixture was stirred for 3h at ambient temperature. After the insoluble matter was filtered off,the solvent was concentrated in vacuo to give the desired product, whichwas used directly in next step without further purification.

Step 7: 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylicacid

To a solution of 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid (7.58 g, 27.05 mmol) in trimethyl orthoformate (50 mL) wasadded p-TsOH (0.23 g, 1.35 mmol). The reaction mixture was stirred for 1h and treated with water (200 mL). The precipitate was filtered off andthe filter cake was washed with water to afford the desired product(7.22 g, 82.7% yield for two steps). ¹H NMR (400 MHz, CDCl₃): δ 8.28 (s,1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.14 (m, 1H), 7.05 (m, 2H), 6.86 (m,1H).

Step 8:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylicacid

To a solution of4-fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid(7.22 g, 24.88 mmol) in DMF (50 mL) was added NIS (6.08 g, 26.37 mmol)followed by trifluoroacetic acid (1.0 mL). After stirring for 5 h atambient temperature, the reaction was quenched by saturated NH₄Cl (aq.).The solution was extracted with ethyl acetate (150 mL×3). The combinedorganic extracts were washed with water (100 mL) and brine (100 mL)successively, dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product (brown solid, 6.34g, 61.2% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.97 (s, 1H), 8.58 (s,1H), 8.18 (s, 1H), 7.58 (dd, J=11.0, 1.7 Hz, 1H), 7.34 (d, J=8.5 Hz,1H), 6.55 (m, 1H).

Step 9:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylicacid (500 mg, 1.2 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h andO-(2-(vinyloxy)ethyl)hydroxylamine (172 mg, 1.62 mmol) was added. Afterstirring for 4 h at ambient temperature, the reaction was treated withsaturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂(30 mL×3). The combined organic extracts were washed with water (30 mL)and brine (30 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by column chromatography on silicagel (CH₂Cl₂/MeOH, 100:1, v/v) and gave the desired product (white solid,450 mg, 74.8% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.82 (s, 1H), 8.96(s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.53 (d, J=10.8 Hz, 1H), 7.28 (d,J=8.1 Hz, 1H), 6.50 (dd, J=13.9, 6.6 Hz, 1H), 6.40 (d, J=6.0 Hz, 1H),4.18 (d, J=14.5 Hz, 1H), 3.99 (m, 3H), 3.83 (s, 2H).

Step 10: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide

To a solution of compound4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide(450 mg, 0.9 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 6.7 mL,6.72 mmol). After stirring for 1 h, the reaction mixture was washed withsaturated NaHCO₃ (aq.). The aqueous layer was washed with CH₂Cl₂ (10mL×2). The combined organic layer was washed with water (10 mL) andbrine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The crude product was purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product (white solid, 380mg, 88.9% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.75 (s, 1H), 8.96 (s,1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.53 (d, J=9.4 Hz, 1H), 7.28 (d, J=8.7Hz, 1H), 6.39 (m, 1H), 4.70 (s, 1H), 3.83 (s, 2H), 3.56 (s, 2H). MS APCI(+) m/z: 476.1, [M+H].

Example 1A Preparation of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide(Compound 1)

Step 1: 1-benzyloxy-2,3,4-trifluorobenzene

Sodium carbonate (19.50 g, 0.184 mol) was dispersed into a solution of2,3,4-trifluorophenol (13.64 g, 0.092 mol) in acetone (300 mL). To thestirred suspension was added the solution of benzyl bromide (17.31 g,101.21 mmol) in acetone (100 mL) dropwisely. The mixture was heatedunder reflux at 50° C. for 24 h, allowed to cool to room temperature,and filtered. The filter cake was washed with acetone (50 mL×3), andacetone was removed under reduced pressure. The residue was dissolved inethyl acetate (500 mL). The solution was washed with 5% sodium hydroxide(50 mL), water (150 mL) and brine (150 mL) sequentially and dried overNa₂SO₄. The solvent was removed in vacuo to yield a pale yellow solid(19.89 g, 90% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.40 (m, 5H), 6.85 (m,1H), 6.64 (m, 1H), 5.15 (s, 2H).

Step 2: 5-benzyloxy-2,3,4-trifluorobenzoic acid

To a solution of 1-benzyloxy-2,3,4-trifluorobenzene (19.89 g, 83.6 mmol)in anhydrous THF (120 mL) was added lithium diisopropylamide (2.0 M inTHF, 42.6 mL, 85.2 mmol) at −78° C. under nitrogen atmosphere. Afterstirring for 1 h at −78° C., the mixture was transferred to a bottlewith dry ice (20.0 g, 454.5 mmol). The mixture was stirred overnight atambient temperature. The reaction was quenched with 10% aqueous HCl (300mL). The mixture was extracted with ethyl acetate (200 mL×3). Thecombined organic extracts were washed with 5% sodium hydroxide (300 mL).The aqueous layer was acidized to pH 1 with concentrated HCl (aq.) andextracted with ethyl acetate (200 mL×3). The combined organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure toafford the desired product (white solid, 19.33 g, 82% yield). ¹H NMR(400 MHz, CDCl₃): δ 14.01 (s, 1H), 7.42 (6H, m), 5.16 (2H, s).

Step 3: 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (13.21 g, 137.1 mmol) and5-benzyl-oxy-2,3,4-trifluorobenzoic acid (19.33 g, 68.55 mmol) in THF(120 mL) at −78° C. was added LiHMDS (206.1 mL, 1 M in THF, 206.1 mmol)dropwisely. The mixture was allowed to slowly warm to room temperatureand stirred at this temperature overnight. The reaction was quenchedwith HCl (aq., 1 N, 250 mL) and extracted with ethyl acetate (200 mL×3).The combined organic extracts were washed with water (200 mL×3) andbrine (200 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated in vacuo to afford the desired product (pale yellow solid,19.17 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 13.76 (s, 1H), 8.58(s, 1H), 7.61 (dd, J=8.8, 1.7 Hz, 1H), 7.52-7.35 (m, 5H), 7.20 (m, 1H),7.05 (m, 1H), 6.98-6.82 (m, 2H), 5.26 (s, 2H).

Step 4: benzyl5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (19.17 g,51.35 mmol) in DMF (30 mL) was added potassium bicarbonate (6.16 g,61.62 mmol) followed by benzyl bromide (6.2 mL, 51.41 mmol). The mixturewas stirred for 5 h at room temperature and then water (150 mL) wasadded. The solution was extracted with ethyl acetate (150 mL×3). Thecombined organic extracts were washed with water (100 mL×3) and brine(200 mL) sequentially, dried over Na₂SO₄, filtered and concentrated invacuo to afford the corresponding product (21.42 g, 90% yield). ¹H NMR(400 MHz, CDCl₃): δ 8.51 (s, 1H), 7.51 (dd, J=8.5, 2.1 Hz, 1H),7.46-7.36 (m, 10H), 7.12-7.06 (m, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 6.85(m, 1H), 5.33 (s, 2H), 5.15 (s, 2H).

Step 5: benzyl4-azido-5-benzyloxy-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of benzyl5-benzyloxy-3,4-difluoro-2-((2-fluoro-phenyl)amino)benzoate (21.42 g,46.26 mmol) in DMF (35 mL) was added NaN₃ (3.61 g, 55.51 mmol). Themixture was stirred at 90° C. for 3 h. Then water (300 mL) was added.The solution was extracted with ethyl acetate (150 mL×3). The combinedorganic extracts were washed with water (100 mL×3) and brine (200 mL)sequentially, dried over Na₂SO₄ and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (petroleumether/ethyl acetate, 10:1, v/v) and gave the desired product (whitesolid, 14.63 g, 65% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.55 (s, 1H),7.53 (dd, J=8.5, 2.1 Hz, 1H), 7.50-7.33 (m, 10H), 7.09 (m, 1H), 7.05 (m,1H), 6.90 (m, 1H), 6.83 (m, 1H), 5.35 (s, 2H), 5.20 (s, 2H).

Step 6: 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxy benzoicacid

To a solution of benzyl4-azido-5-benzyloxy-3-fluoro-2-((2-fluorophenyl)amino)benzoate (14.63 g,30.07 mmol) in MeOH (200 mL) was added and 10% palladium on carbon (2.55g) under nitrogen atmosphere. Then the nitrogen atmosphere wascompletely changed to hydrogen atmosphere. The mixture was stirred for 6h at ambient temperature. After the insoluble matter was filtered off,the solvent was concentrated in vacuo to give the crude product (7.58 g,90% yield), which was used directly in next step without furtherpurification.

Step 7: 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylicacid

To a solution of 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid (7.58 g, 27.08 mmol) in trimethyl orthoformate (50 mL) wasadded p-TsOH (233 mg, 1.35 mmol). The reaction mixture was stirred for 1h and treated with water (300 mL). The precipitate was filtered off andthe filter cake was washed with water to afford the desired product(7.22 g, 92% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.28 (s, 1H), 8.27 (s,1H), 8.24 (s, 1H), 7.14 (m, 1H), 7.11 (m, 1H), 7.04 (m, 1H), 6.85 (m,1H).

Step 8: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzooxazole-6-carboxylic acid

To a solution of4-fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid(7.22 g, 24.90 mmol) in DMF (50 mL) was added NIS (6.08 g, 26.37 mmol)followed by trifluoroacetic acid (3 mL). After stirring for 4 h atambient temperature, the reaction was quenched with saturated NH₄Cl(aq., 100 mL). The solution was extracted with ethyl acetate (150 mL×3).The combined organic extracts were washed with water (50 mL×3) and brine(100 mL) successively, dried over Na₂SO₄ and concentrated in vacuo. Thecrude product was purified by column chromatography on silica gel(petroleum ether/ethyl acetate, 3:1, v/v) and gave the desired product(brown solid, 6.339 g, 69% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.97 (s,1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.58 (dd, J=11.0, 1.7 Hz, 1H), 7.34 (d,J=8.5 Hz, 1H), 6.55 (m, 1H).

Step 9:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzooxazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylicacid (500 mg, 1.2 mmol) in CH₂Cl₂ was added HOBt (254 mg, 1.63 mmol) andEDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h andO-(2-(vinyloxy)ethyl)hydroxylamine (172 mg, 1.62 mmol) was added. Afterstirring for 4 h at ambient temperature, the reaction was treated withsaturated NH₄Cl (aq., 20 mL). The resultant mixture was extracted withCH₂Cl₂ (30 mL×3). The combined organic extracts were washed with water(30 mL×2) and brine (30 mL) sequentially, dried over Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) and gave thedesired product (white solid, 598 mg, 98% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 11.82 (s, 1H), 8.96 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H),7.53 (d, J=10.8 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 6.50 (dd, J=13.9, 6.6Hz, 1H), 6.40 (d, J=6.0 Hz, 1H), 4.18 (d, J=14.5 Hz, 1H), 3.99 (m, 3H),3.83 (s, 2H).

Step 10:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzooxazole-6-carboxamide

To a solution of compound4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide(598 mg, 1.17 mmol) in CH₂Cl₂ (5 mL) was added 1.0 N HCl (aq., 6.7 mL,6.72 mmol) dropwise. After stirring for 1 h, the reaction mixture wastreated with saturated NaHCO₃ (aq.). The organic layer was washed withwater (30 mL×2) and brine (30 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH, 15:1, v/v) and gave thedesired product (white solid, 290 mg, 52% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 11.75 (s, 1H), 8.96 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H),7.53 (d, J=9.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 6.39 (m, 1H), 4.70 (s,1H), 3.83 (m, 2H), 3.56 (m, 2H). MS (ES+): m/z 476.34 [MH⁺].

Example 2 Preparation ofN-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide(Compound 2)

Step 1:N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylicacid (500 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (238 mg,1.62 mmol) was added. After stirring for 4 h at ambient temperature, thereaction was treated with saturated NH₄Cl (aq.). The resultant mixturewas extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts waswashed by water (30 mL) and brine (30 mL) sequentially, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product (488 mg)was used directly in the next step without further purification.

Step 2:N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide

To a solution ofN-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide(488 mg, 0.89 mmol) in CH₂Cl₂ (10 mL) was added trifluoroacetic acid(0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and washed withsaturated sodium bicarbonate (aq.). The aqueous layer was extracted byCH₂Cl₂ (10 mL×2). The combined organic layers were washed by water (10mL) and brine (10 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) to afford thedesired product (white solid, 310 mg, 48% yield for two steps). ¹H NMR(400 MHz, DMSO-d₆): δ 11.80 (s, 1H), 8.96 (s, 1H), 8.03 (s, 1H), 7.87(s, 1H), 7.53 (d, 1H), 7.28 (d, 1H), 6.40 (m, 1H), 4.84 (d, 1H), 4.60(m, 1H), 3.87 (m, 1H), 3.72 (m, 2H), 3.36 (m, 2H). MS APCI (+) m/z:527.8, [M+Na].

Example 3 Preparation of5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide(Compound 3)

Step 1: 5-(benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoic acid

To a solution of 2-chloroaniline (13.91 ml, 137.00 mmol) and5-benzyloxy-2,3,4-trifluorobenzoic acid (19.33 g, 68.50 mmol) in THF(120 mL) at −78° C. was added LiHMDS (205.5 mL, 1 M in THF, 205.5 mmol)dropwisely under nitrogen atmosphere. The mixture was slowly warmed toroom temperature and stirred at this temperature overnight. The reactionwas quenched with water (100 mL) and acidified to pH 2-3 with 10% HCl(aq.). The mixture was extracted with ethyl acetate (100 mL×3). Thecombined organic extracts were washed with water (100 mL) and brine (100mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuoto afford the desired product (pale yellow solid, 23.80 g, 89.1% yield).¹H NMR (400 MHz, DMSO-d₆): δ 13.80 (s, 1H), 8.66 (s, 1H), 7.64 (m, 1H),7.34 (m, 7H), 6.92 (m, 1H), 6.78 (m, 1H), 5.26 (s, 2H).

Step 2: benzyl5-(benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoate

To a solution of5-(benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoic acid (23.80g, 61.06 mmol) in DMF (200 mL) was added potassium bicarbonate (9.16 g,91.6 mmol) followed by benzyl bromide (8.0 mL, 67.37 mmol). The mixturewas stirred for 5 h at room temperature and water (300 mL) was added.The solution was extracted with ethyl acetate (100 mL×3). The combinedorganic extracts were washed with water (200 mL×3) and brine (200 mL)sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo.After purification by column chromatography on silica gel (petroleumether/ethyl acetate, 50:1, v/v), the corresponding product was obtainedas white solid (27.82 g, 95% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.56 (s,1H), 7.52 (dd, J=8.5, 2.1 Hz, 1H), 7.40 (m, 11H), 7.15 (m, 1H), 6.88 (m,1H), 6.74 (m, 1H), 5.34 (s, 2H), 5.16 (s, 2H).

Step 3: benzyl4-azido-5-(benzyloxy)-2-((2-chlorophenyl)amino)-3-fluorobenzoate

To a solution of benzyl5-(benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoate (27.82 g,57.97 mmol) in DMF (250 mL) was added NaN₃ (4.52 g, 69.56 mmol). Themixture was stirred at 90° C. for 3 h. Then water (400 mL) was added.The solution was extracted with ethyl acetate (150 mL×3). The combinedorganic extracts were washed with water (150 mL) and brine (150 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (petroleumether/ethyl acetate, 50:1, v/v) and gave the desired product (paleyellow solid, 22.97 g, 78.8% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.41 (s,1H), 7.40 (m, 12H), 7.13 (m, 1H), 6.87 (m, 1H), 6.69 (m, 1H), 5.34 (s,2H), 5.17 (s, 2H).

Step 4: 4-amino-2-((2-chlorophenyl)amino)-3-fluoro-5-hydroxy benzoicacid

To a solution of compound benzyl4-azido-5-(benzyloxy)-2-((2-chlorophenyl)amino)-3-fluorobenzoate (22.97g, 45.67 mmol) in MeOH (500 mL) was added and 10% palladium on carbon(3.80 g) under nitrogen atmosphere. Then the nitrogen atmosphere wascompletely changed to hydrogen atmosphere. The mixture was stirred for 3h at ambient temperature. After the insoluble matter was filtered off,the solvent was evaporated under reduced pressure to give the desiredproduct, which was used directly in the next step without furtherpurification.

Step 5: 5-((2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylicacid

To a solution of4-amino-2-((2-chlorophenyl)amino)-3-fluoro-5-hydroxybenzoic acid intrimethyl orthoformate (100 mL) was added p-TsOH (0.42 g, 1.35 mmol).The reaction mixture was stirred for 1 h and treated with water (300mL). The precipitate was filtered off and the filter cake was washedwith water to afford a yellow solid (12.31 g, 87.9% yield for twosteps). ¹H NMR (400 MHz, DMSO-d₆): δ 13.9 (s, 1H), 9.05 (s, 1H), 8.8 (s,1H), 8.23 (s, 1H), 7.43 (m, 1H), 7.15 (m, 1H), 6.98 (m, 1H), 6.74 (m,1H).

Step 6:5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylicacid

To a solution of5-((2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid(12.31 g, 40.14 mmol) in DMF (100 mL) was added NBS (7.86 g, 44.15mmol). After stirring for 4 h at ambient temperature, the reaction wasquenched by water and the precipitate was filtered. The crude productwas purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 50:1,v/v) and gave the desired product (pale brown solid, 10.82 g, 69.9%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), 9.42 (s, 1H), 8.96(s, 1H), 8.27 (s, 1H), 7.82 (d, J=12.0 Hz, 1H), 7.37 (m, 1H), 6.65 (m,1H).

Step 7:5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-(vinyl-oxy)ethoxy)benzo[d]oxazole-6-carboxamide

To a solution of5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylicacid (463 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h andO-(2-(vinyloxy)ethyl)hydroxylamine (172 mg, 1.62 mmol) was added. Afterstirring for 4 h at ambient temperature, the reaction was treated withsaturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂(30 mL×3). The combined organic extracts were washed with water (30 mL)and brine (30 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The crude product (445 mg) was used directly in the next stepwithout further purification.

Step 8:5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide

To a solution of5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide(445 mg, 0.95 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl solution (6.7mL, 6.72 mmol). After stirring for 1 h, the reaction mixture was washedwith saturated NaHCO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂(10 mL×2). The combined organic layer was washed with water (10 mL) andbrine (10 mL) successively, dried over Na₂SO₄, filtered and concentratedin vacuo. The crude product was purified by column chromatography onsilica gel (CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product (whitesolid, 347 mg, 65% yield for two steps). ¹H NMR (400 MHz, MeOD): δ 8.65(s, 1H), 7.8 (s, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.24 (m, 1H), 6.50 (m,1H), 3.95 (s, 2H), 3.70 (s, 2H). MS APCI (+) m/z: 445.9[M+H], 467.8,[M+Na].

Example 4 Preparation of5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide(Compound 4)

Step 1:5-((4-bromo-2-chlorophenyl)amino)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluorobenzo[d]oxazole-6-carboxamide

To a solution of5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylicacid (463 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for1 h and O-((2,2-dimethyl-1,3-di-oxolan-4-yl)methyl)hydroxylamine (238mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature,the reaction was treated with saturated NH₄Cl (aq.). The resultantmixture was extracted with CH₂Cl₂ (30 mL×3). The combined organicextracts was washed by water (30 mL) and brine (30 mL) sequentially,dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product(473 mg) was used directly in the next step without furtherpurification.

Step 2:5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide

To a solution of5-((4-bromo-2-chlorophenyl)amino)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluorobenzo[d]oxazole-6-carboxamide(473 mg, 0.92 mmol) in CH₂Cl₂ (10 mL) was added trifluoroacetic acid(0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and washed withsaturated sodium bicarbonate (aq.). The aqueous layer was extracted byCH₂Cl₂ (10 mL×2). The combined organic layers were washed by water (10mL) and brine (10 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) to afford thedesired product (white solid, 255 mg, 44.7% yield for two steps). ¹H NMR(400 MHz, DMSO-d₆): δ 11.78 (s, 1H), 8.95 (s, 1H), 8.05 (s, 1H), 7.89(s, 1H), 7.54 (d, 1H), 7.30 (d, 1H), 6.42 (m, 1H), 4.83 (d, 1H), 4.62(m, 1H), 3.86 (m, 1H), 3.70 (m, 2H), 3.35 (m, 2H). MS APCI (+) m/z:475.7, [M+H].

Example 5 Preparation ofN-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropanesulfonamide(Compound 5)

Step 1:4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylicacid (70 mg, 0.17 mmol) in t-BuOH (3 mL) was added DPPA (82 mg, 0.29mmol) followed by triethylamine (36 mg, 0.36 mmol). The mixture washeated under reflux for 3 h and allowed to slowly warm to roomtemperature. The solvent was removed in vacuo and the resultant crudeproduct was purified by column chromatography on silica gel (petroleumether/ethyl acetate, 2:1, v/v). The corresponding product was obtained(white solid, 62 mg, 89.2% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.75(s, 1H), 8.67 (s, 1H), 7.96 (d, 1H), 7.76 (d, 1H), 7.50 (m, 1H), 7.39(s, 1H).

Step 2:7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one(30 mg, 0.07 mmol) in CH₂Cl₂ (3 mL) was added triethylamine (22 mg, 0.22mmol) at 0° C. followed by cyclopropanesulfonyl chloride (16 mg, 0.11mmol) and DMAP (5 mg). The mixture was stirred at room temperature for 1h and washed with saturated NaHCO₃ (aq.). The aqueous layer wasextracted with CH₂Cl₂ (10 mL×2). The combined organic phase was washedwith water (10 mL) and brine (10 mL) successively, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v)to give the corresponding product (40 mg, 100% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.39-7.11 (d, 2H), 7.05, (m, 1H),3.40 (m, 1H), 1.71 (m, 2H), 0.91-0.85 (m, 2H).

Step 3:N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropanesulfonamide

To a solution of 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (30 mg, 0.06mmol) in THF (3 mL) was added potassium trimethylsilanolate (12 mg, 0.09mmol). After stirring at room temperature for 1 h, the reaction wasquenched with saturated NH₄Cl (aq.). The aqueous layer was extractedwith ethyl acetate (5 mL×2). The combined organic phase was washed withbrine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The residual crude product was purified by flash chromatography onsilica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give thecorresponding product as a white solid (10 mg, 35.1% yield). ¹H NMR (400MHz, CDCl₃): δ 8.15 (s, 1H), 7.88 (s, 1H), 7.46 (dd, 1H), 7.33 (s, 1H),7.23 (dd, 1H), 6.15 (m, 1H), 5.49 (s, 1H), 2.55 (m, 1H), 1.01 (m, 2H),0.92 (m, 2H). MS APCI (+) m/z: 492.5, [M+H].

Example 6 Preparation of1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide(Compound 6)

Step 1:7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one(100 mg, 0.24 mmol) in DCM (5 mL) was added triethylamine (74 mg, 0.73mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (66mg, 0.36 mmol) and DMAP (15 mg). After stirring at room temperature for1 h, the mixture was washed with saturated NaHCO₃ (aq.). The aqueouslayer was extracted with DCM (20 mL×2). The combined organic phase waswashed by water (20 mL) and brine (20 mL) sequentially, dried overNa₂SO₄, filtered and concentrated to give a residue, which was purifiedby flash chromatography on silica gel (petroleum ether/ethyl acetate,5:1, v/v) to give the corresponding product (120 mg, 89.0% yield). ¹HNMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.70-7.68 (d, 2H),7.27 (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H),2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).

Step 2:1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide

To a solution of7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one(120 mg, 0.23 mmol) in THF (10 mL) was added potassiumtrimethylsilanolate (48 mg, 0.35 mmol). The reaction was stirred at roomtemperature for 1 h and quenched with saturated NH₄Cl (aq.). The aqueouslayer was extracted with EA (10 mL×2). The combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by flash chromatography on silica gel(petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the desiredproduct (100 mg, 87.0% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H),7.99 (s, 1H), 7.42 (m, 1H), 7.31-7.25 (m, 1H), 6.80 (s, 1H), 6.43-6.35(m, 1H), 6.21 (s, 1H), 5.85-5.70 (m, 1H), 5.22-5.14 (m, 2H), 2.83 (d,2H), 1.28-1.20 (m, 2H), 0.87-0.80 (m, 2H).

Step 3:1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophen-yl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide

To a solution of1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide(100 mg, 0.38 mmol) in THF (10 mL) was added N-methylmorpholine-N-oxide(44 mg, 0.38 mmol) followed by osmium tetraoxide (10 mg, 0.04 mmol) andwater (0.5 mL). The resultant was stirred at room temperature overnight.The mixture was concentrated and then diluted with ethyl acetate. Theorganic layer was washed with water, saturated NaHCO₃ (aq.) and brinesequentially, dried over Na₂SO₄, filtered and concentrated to give aresidue, which was purified by flash chromatography on silica gel togive the product as white solid (30 mg, 28.2% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.46-7.36 (m, 2H), 7.30-7.20 (m,1H), 6.82 (s, 1H), 6.45-6.32 (m, 1H), 4.40-4.26 (m, 2H), 4.20-4.10 (m,1H), 3.75-3.60 (m, 1H), 2.86-2.79 (m, 1H), 1.30-1.25 (m, 2H), 1.15-1.20(m, 4H). MS APCI (+) m/z: 566.3, [M+H].

Example 7 Preparation ofN-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazol-6-yl)cyclopropanesulfonamide(Compound 7)

Step 1:5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylicacid (110 mg, 0.28 mmol) in t-BuOH (3 mL) was added DPPA (94 mg, 0.34mmol) followed by triethylamine (58 mg, 0.57 mmol). The mixture washeated under reflux for 3 h and allowed to slowly warm to roomtemperature. The solvent was removed in vacuo and the resultant crudeproduct was purified by column chromatography on silica gel (petroleumether/ethyl acetate, 2:1, v/v). The corresponding product was obtained(white solid, 105 mg, 96.2% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.78(s, 1H), 8.69 (s, 1H), 7.99 (d, 1H), 7.77 (d, 1H), 7.51 (m, 1H), 7.41(s, 1H).

Step 2:5-(4-bromo-2-chlorophenyl)-7-(cyclopropylsulfonyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one(100 mg, 0.26 mmol) in CH₂Cl₂ (10 mL) was added triethylamine (80 mg,0.78 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (55 mg,0.39 mmol) and DMAP (10 mg). The mixture was stirred at room temperaturefor 1 h and washed with saturated NaHCO₃ (aq.). The aqueous layer wasextracted with CH₂Cl₂ (15 mL×2). The combined organic phase was washedwith water (15 mL) and brine (20 mL) successively, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v)to give the corresponding product (110 mg, 86.5% yield). ¹H NMR (400MHz, CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.71-7.69 (m, 2H), 7.32 (m,1H), 3.35 (m, 1H), 1.69 (m, 2H), 0.88 (m, 2H).

Step 3:N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]oxazol-6-yl)cyclopropanesulfonamide

To a solution of5-(4-bromo-2-chlorophenyl)-7-(cyclopropylsulfonyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one(100 mg, 0.21 mmol) in THF (10 mL) was added potassiumtrimethylsilanolate (40 mg, 0.31 mmol). After stirring at roomtemperature for 1 h, the reaction was quenched with saturated NH₄Cl(aq.). The aqueous layer was extracted with ethyl acetate (10 mL×2). Thecombined organic phase was washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residual crude product waspurified by flash chromatography on silica gel (petroleum ether/ethylacetate, 5:1-3:1, v/v) and the product was obtained as a white solid (60mg, 63.4% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1H), 7.97 (s, 1H),7.40 (m, 2H), 7.31-7.26 (m, 1H), 6.81 (s, 1H), 6.40-6.36 (m, 1H), 6.23(s, 1H), 5.86-5.72 (m, 1H), 5.25-5.13 (m, 2H), 2.85 (d, 2H), 1.30-1.22(m, 2H), 1.15-1.20 (m, 2H). 8.17 (s, 1H), 7.97 (s, 1H), 7.49 (dd, 1H),7.35 (s, 1H), 7.26 (dd, 1H), 6.17 (m, 1H), 5.44 (s, 1H), 2.57 (m, 1H),1.06-1.08 (m, 2H), 1.00-1.01 (m, 2H). MS APCI (+) m/z: 461.7, [M+H].

Example 8 Preparation ofN-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide(Compound 8)

Step 1:7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one(100 mg, 0.26 mmol) in DCM (10 mL) was added triethylamine (80 mg, 0.78mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (71mg, 0.39 mmol) and DMAP (15 mg). After stirring at room temperature for1 h, the reaction was treated with saturated NaHCO₃ (aq.). The aqueouslayer was extracted with CH₂Cl₂ (20 mL×2). The combined organic phasewas washed with water (20 mL) and brine (20 mL) sequentially, dried overNa₂SO₄, filtered and concentrated to give a residue, which was purifiedby flash chromatography on silica gel (petroleum ether/ethyl acetate,5:1, v/v) to give the corresponding product (120 mg, 87.2% yield). ¹HNMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.39-7.11 (d, 2H),7.05, (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H),2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).

Step 2:1-allyl-N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide

To a solution of7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-chloro-4-bromophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one(120 mg, 0.23 mmol) in THF (5 mL) was added potassiumtrimethylsilanolate (32 mg, 0.23 mmol). The mixture was stirred at roomtemperature for 1 h and treated with saturated NH₄Cl (aq.). The aqueouslayer was extracted with ethyl acetate (10 mL×2). The combined organicphase was washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to give a residue, which was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1,v/v) to give the product as a white solid (100 mg, 87.6% yield). ¹H NMR(400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.42 (d, 1H), 7.31-7.25(m, 1H), 6.80 (s, 1H), 6.43-6.35 (m, 1H), 6.21 (s, 1H), 5.85-5.70 (m,1H), 5.22-5.14 (m, 2H), 2.83 (d, 2H), 1.28-1.20 (m, 2H), 0.87-0.80 (m,2H).

Step 3: 1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide

To a solution of1-allyl-N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide(100 mg, 0.38 mmol) in THF (10 mL) was added N-methylmorpholine-N-oxide(44 mg, 0.38 mmol) followed by osmium tetraoxide (10 mg, 0.04 mmol) andwater (0.5 mL). After stirring at room temperature overnight, themixture was concentrated and then diluted with EA. The organic layer waswashed with water, saturated NaHCO₃ (aq.) and brine sequentially, driedover Na₂SO₄, filtered and concentrated to give a residue, which waspurified by flash chromatography to give the product as white solid (30mg, 28.2% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1H), 7.98 (s, 1H),7.45-7.34 (m, 2H), 7.32-7.21 (m, 1H), 6.83 (s, 1H), 6.44-6.30 (m, 1H),4.41-4.25 (m, 2H), 4.21-4.12 (m, 1H), 3.72-3.62 (m, 1H), 2.85-2.78 (m,1H), 1.32-1.26 (m, 2H), 1.16-1.21 (m, 4H). MS APCI (+) m/z: 535.8,[M+H].

Example 9 Preparation of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide(Compound 9)

Step 1: 5-bromo-2,3,4-trifluorobenzoic acid

To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL)was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C.under nitrogen atmosphere. The stirring was maintained at thistemperature for 1 h. Then a solution of 1-bromo-2,3,4-trifluorobenzene(17.62 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 hat −78° C., the mixture was transferred to a bottle with dry ice. Themixture was stirred overnight at room temperature. The reaction wasquenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixturewas extracted with ethyl acetate (100 mL×3). The combined organicextracts were washed with water (100 mL) and brine (100 mL)sequentially, dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford the desired product (20.12 g, 94.5% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 13.95 (s, 1H), 7.97 (m, 1H).

Step 2: 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (17.54 g, 157.80 mmol) and5-bromo-2,3,4-trifluorobenzoic acid (20.12 g, 78.90 mmol) in THF (120mL) was added LiHMDS (236.7 mL, 1 M in THF, 236.7 mmol) dropwisely at−78° C. under nitrogen atmosphere. The mixture was allowed to slowlywarm to room temperature and stirred at this temperature overnight. Thereaction was quenched with water (100 mL) and acidified to pH 2-3 with10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL×3).The combined organic extracts were washed with water (100 mL) and brine(100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated invacuo to afford the desired product (pale yellow solid, 24.24 g, 88.8%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.22 (s, 1H), 8.01 (dd, J=7.4, 2.1Hz, 1H), 7.25 (m, 1H), 7.10 (m, 3H).

Step 3: methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoicacid (24.24 g, 70.04 mmol) in MeOH (300 mL) was added thionyl chloride(20 mL). After stirring at 85° C. overnight, most MeOH was removed invacuo. The residue was neutralized with saturated sodium bicarbonate(aq.) and extracted with ethyl acetate (100 mL×3). The combined organiclayer was washed with water (100 mL) and brine (100 mL) sequentially,dried over Na₂SO₄, filtered and concentrated. After purification bycolumn chromatography on silica gel (petroleum ether/ethyl acetate,50:1, v/v), the corresponding product was obtained as a white solid(22.33 g, 88.5% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.06 (s, 1H), 8.01(dd, J=7.1, 2.3 Hz, 1H), 7.04 (m, 4H), 3.92 (s, 3H).

Step 4: methyl3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate

To a solution of methyl5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (22.33 g, 62.01mmol) in anhydrous 1,4-dioxane (200 mL) was addedN,N-diisopropylethylamine (16.03 g, 124.04 mmol). Then Pd₂(dba)₃ (2.84g, 3.10 mmol) followed by Xantphos (3.59 g, 6.20 mmol) and4-methoxy-α-toluenethiol (10.27 g, 65.11 mmol) was added under nitrogenatmosphere. The mixture was stirred overnight at 100° C. under N₂atmosphere and then allowed to warm to ambient temperature. Theinsoluble matter was filtered off and the filter cake was washed ethylacetate. The filtrate was diluted with water (300 mL) and extracted withethyl acetate (100 mL×3). The combined organic layers were washed withwater (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄,filtered and concentrated. The crude product was purified by columnchromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v)to give the desired product (pale yellow solid, 24.35 g, 90.6% yield).¹H NMR (400 MHz, CDCl₃): δ 9.12 (s, 1H), 7.78 (d, 1H), 7.25 (m, 6H),6.85 (m, 2H), 4.03 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H).

Step 5: methyl4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl5-(4-methoxybenzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate(24.35 g, 56.18 mmol) in DMF (200 mL) was added NaN₃ (4.38 g, 67.41mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h.Then water (200 mL) was added. The solution was extracted with ethylacetate (100 mL×3). The combined organic extracts were washed with water(100 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desiredproduct (white solid, 21.04 g, 82.1% yield). ¹H NMR (400 MHz, CDCl₃): δ8.98 (s, 1H), 7.75 (s, 1H), 7.10 (m, 6H), 6.84 (m, 2H), 4.03 (s, 2H),3.92 (s, 3H), 3.81 (s, 3H).

Step 6: methyl4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate(21.04 g, 46.09 mmol) in MeOH (500 mL) was added and 10% palladium oncarbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmospherewas completely changed to hydrogen atmosphere. The mixture was stirredfor 2 h at ambient temperature. After the insoluble matter was filteredoff, the solvent was evaporated in vacuo to give the desired product(19.46 g, 98.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.07 (s, 1H), 7.77(s, 1H), 7.06 (m, 4H), 6.95 (m, 2H), 6.81 (d, J=8.3 Hz, 2H), 4.68 (s,2H), 3.85 (s, 5H), 3.81 (s, 3H).

Step 7: dimethyl5,5′-disulfanediylbis(4-amino-3-fluoro-2-((2-fluorophenyl)amino)benzoate)

To a solution of methyl4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate(19.46 g, 45.21 mmol) in CH₂Cl₂ (180 mL) was added DDQ (11.29 g, 49.73mmol) followed by water (20 mL). After stirring at ambient temperaturefor 10 h, the reaction was quenched by saturated sodium bicarbonate(aq., 100 mL). The aqueous layer was extracted by CH₂Cl₂ (100 mL×3). Thecombined organic phase was washed with water (100 mL) and brine (100 mL)sequentially, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography on silica gel (petroleumether/ethyl acetate, 5:1, v/v) to give the desired product (pale yellowsolid, 9.81 g, 35.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.34 (s, 2H),7.46 (s, 2H), 7.06 (m, 8H), 4.89 (br, 4H), 3.75 (s, 6H).

Step 8: methyl4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate

To a solution of dimethyl5,5′-disulfanediylbis(4-amino-3-fluoro-2-((2-fluorophenyl)amino)benzoate)(9.81 g, 15.86 mmol) in THF/MeOH (100 mL, 10:1, v/v) was added NaBH₄(3.00 g, 79.29 mmol) portion-wise in 1 h. After stirring at ambienttemperature for 1 h, the reaction was quenched with 10% HCl (aq.) and pHwas adjusted to 1-2. The aqueous layer was extracted with CH₂Cl₂ (50mL×3). The combined organic phase was washed with water (50 mL) andbrine (50 mL) sequentially, dried over Na₂SO₄, filtered and concentratedin vacuo. The crude product was used directly in the next step withoutfurther purification.

Step 9: methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate

To a solution of methyl4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate intrimethyl orthoformate (50 mL) was added p-TsOH (0.61 g, 3.17 mmol). Thereaction mixture was stirred for 1 h and treated with water (100 mL).The precipitate was filtered off and the filter cake was washed withwater to afford the desired product (pale yellow solid, 8.64 g, 85.1%yield for two steps). ¹H NMR (400 MHz, CDCl₃): δ 9.13 (s, 1H), 8.68 (s,1H), 8.46 (s, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 6.92 (s, 2H), 3.97 (s,3H).

Step 10: methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate

To a solution of methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate (8.64g, 26.97 mmol) in DMF (100 mL) was added NIS (6.68 g, 29.67 mmol)followed by trifluoroacetic acid (0.5 mL). After stirring for 5 h atambient temperature, the reaction was treated by water (150 mL). Theprecipitate was filtered off and the filter cake was washed with water.The desired product was obtained as a yellow solid (10.34 g, 86.0%yield). ¹H NMR (400 MHz, CDCl₃): δ 9.14 (s, 1H), 8.66 (s, 1H), 8.46 (s,1H), 7.42 (d, J=10.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.63 (dd, J=15.0,8.7 Hz, 1H), 3.97 (s, 3H).

Step 11:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylicacid

To a solution of methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate(10.34 g, 23.17 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 MLiOH (aq., 2 mL, 10 mmol). After stirring at ambient temperature for 2h, the reaction was treated with 1.0 M HCl (aq.) till the solution wasacidic. The aqueous layer was extracted with ethyl acetate (50 mL×3).The combined organic phase was washed with water (100 mL) and brine (100mL) sequentially, dried over Na₂SO₄, filtered and concentrated to givethe desired product (9.51 g, 95.0% yield). ¹H NMR (400 MHz, DMSO-d₆): δ11.10 (s, 1H), 9.18 (s, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 7.41 (m, 1H),7.30 (m, 1H), 6.65 (m, 1H).

Step 12:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylicacid (519 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h andO-(2-(vinyloxy)ethyl)hydroxyl-amine (172 mg, 1.62 mmol) was added. Afterstirring for 4 h at ambient temperature, the reaction was treated withsaturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂(30 mL×3). The combined organic extracts were washed with water (30 mL)and brine (30 mL), dried over Na₂SO₄ filtered, and concentrated invacuo. The crude product (492 mg) was used directly in the next stepwithout further purification.

Step 13:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide(492 mg, 1.00 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 5 mL, 5mmol). After stirring for 1 h, the reaction mixture was neutralized withsaturated NaHCO₃ (aq.). The aqueous layer was washed with CH₂Cl₂ (30mL). The combined organic layer was washed with water (30 mL×2) andbrine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The crude product was purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product as a white solid(446 mg, 75.9% yield for the two steps). ¹H NMR (400 MHz, DMSO-d₆): δ11.80 (s, 1H), 9.55 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.55 (d, J=11.0Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 6.48 (d, J=9.2 Hz, 1H), 4.72 (s, 1H),3.84 (m, 2H), 3.57 (m, 2H). MS APCI (+) m/z: 491.8, [M+H].

Example 9A Preparation of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide(Compound 9)

Step 1: 5-bromo-2,3,4-trifluorobenzoic acid

To a solution of 1-bromo-2,3,4-trifluorobenzene (13.64 g, 64.6 mmol) inTHF (120 mL) was added lithium diisopropylamide (2.0 M in THF, 33.9 mL,67.8 mmol) at −78° C. under nitrogen atmosphere. After stirring for 1 hat −78° C., the mixture was transferred to a bottle with dry ice. Themixture was stirred overnight at room temperature. The reaction wasquenched with 10% aqueous HCl (300 mL) and extracted with ethyl acetate(200 mL×3). The combined organic extracts were washed with 5% sodiumhydroxide (300 mL). The aqueous layer was acidized to pH 1 and extractedwith ethyl acetate (200 mL×3). The combined organic extract was driedover Na₂SO₄, filtered and concentrated under reduced pressure to affordthe desired product (white solid, 13.51 g, 82% yield). ¹H NMR (400 MHz,CDCl₃): δ 13.94 (s, 1H), 7.95 (m, 1H).

Step 2: 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (10.2 mL, 105.8 mmol) and5-bromo-2,3,4-trifluorobenzoic acid (13.51 g, 52.9 mmol) in THF (120 mL)was added LiHMDS (158.7 mL, 1 M in THF, 158.7 mmol) dropwisely at −78°C. under nitrogen atmosphere. The mixture was allowed to slowly warm toroom temperature and stirred at this temperature overnight. The reactionwas quenched with 10% HCl (aq., 100 mL) and extracted with ethyl acetate(200 mL×3). The combined organic extracts were washed with water (200mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated in vacuo to afford the desired product (pale yellow solid,13.73 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.21 (s, 1H), 8.01 (d,1H), 7.26 (m, 1H), 7.01-7.16 (m, 3H).

Step 3: methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoicacid (13.73 g, 39.6 mmol) in MeOH (300 mL) was added SOCl₂ (60 mL).After stirring at 85° C. overnight, most MeOH was removed in vacuo. Theresidue was neutralized with saturated sodium bicarbonate (aq.) andextracted with ethyl acetate (300 mL×3). The combined organic extractwas washed with water (200 mL×3) and brine (200 mL) sequentially, driedover Na₂SO₄, filtered and concentrated in vacuo to afford thecorresponding product (gray solid, 12.58 g, 90% yield). ¹H NMR (400 MHz,CDCl₃): δ 9.09 (s, 1H), 8.05 (d, 1H), 7.00-7.14 (m, 4H), 3.94 (s, 3H).

Step 4: methyl3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate

To a solution of methyl5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.85 g, 35.6mmol) in anhydrous 1,4-dioxane (30 mL) was addedN,N-diisopropylethylamine (9.21 g, 71.2 mmol). Then Pd₂(dba)₃ (1.63 g,1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and4-methoxy-α-toluenethiol (5.48 g, 35.6 mmol) was added under nitrogenatmosphere. The mixture was stirred overnight at 100° C. under N₂atmosphere and then allowed to cool to ambient temperature. The reactionwas quenched with water (150 mL) and extracted with ethyl acetate (200mL×3). The combined organic extract was washed with water (200 mL×3) andbrine (200 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography onsilica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give thedesired product (pale yellow solid, 12.64 g, 82% yield). ¹H NMR (400MHz, CDCl₃): δ 9.12 (s, 1H), 7.78 (d, 1H), 7.06-7.44 (m, 6H), 6.82-6.88(m, 2H), 4.03 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H).

Step 5: methyl4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl5-(4-methoxybenzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate(12.64 g, 29.2 mmol) in DMF (30 mL) was added NaN₃ (2.28 g, 35.0 mmol)at ambient temperature. The mixture was stirred at 90° C. for 3 h. Thenwater (150 mL) was added. The solution was extracted with ethyl acetate(100 mL×3). The combined organic extracts were washed with water (100mL×3) and brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product(white solid, 10.38 g, 78% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.98 (s,1H), 7.75 (s, 1H), 7.02-7.28 (m, 6H), 6.83-6.85 (m, 2H), 4.03 (s, 2H),3.92 (s, 3H), 3.81 (s, 3H).

Step 6: methyl4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate(10.38 g, 22.7 mmol) in MeOH (100 mL) was added and 10% palladium oncarbon (1.55 g) under nitrogen atmosphere. Then the nitrogen atmospherewas completely changed to hydrogen atmosphere. The mixture was stirredat ambient temperature for 6 h. After the insoluble matter was filteredoff, the solvent was evaporated in vacuo to give the desired product(9.79 g, 100% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.08 (s, 1H), 7.78 (s,1H), 6.93-7.28 (m, 8H), 4.65 (s, 2H), 4.00 (s, 2H), 3.89 (s, 3H), 3.75(s, 3H).

Step 7: methyl4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate

To a solution of methyl4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate(9.79 g, 22.7 mmol) in anisole (12 mL) was added CF₃COOH (20 mL). Afterstirring at ambient temperature for 23 h, the solvent was removed invacuo. To the residue was added water (30 mL). The mixture wasneutralized with 25% aqueous ammonia and extracted with ethyl acetate(100 mL×3). The combined organic layer was washed with water (100 mL×3)and brine (100 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated to give the desired product (white solid, 5.28 g, 75%yield). The product was used directly in the next step without furtherpurification.

Step 8: methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[c]thiazole-6-carboxylate

To a solution of methyl4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate (2.07 g,6.67 mmol) in trimethyl orthoformate (20 mL) was added p-TsOH (166 mg,0.65 mmol). The reaction mixture was stirred for 1 h and treated withwater (100 mL). The precipitate was filtered off and the filter cake waswashed with water to afford the desired product (white solid, 1.963 g,92% yield for two steps). ¹H NMR (400 MHz, DMSO-d₆): δ 9.01 (s, 1H),8.08 (s, 1H), 7.90 (s, 1H), 7.15-6.78 (m, 4H), 3.91 (s, 3H).

Step 9: methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate

To a solution of methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate (1.963g, 6.14 mmol) in DMF (10 mL) was added NIS (1.5 g, 6.5 mmol) followed bytrifluoroacetic acid (0.5 mL). After stirring for 4 h at ambienttemperature, the reaction was treated by saturated NH₄Cl (aq.). Theaqueous layer was extracted with ethyl acetate (150 mL×3). The combinedorganic layer was washed with water (100 mL×3) and brine (100 mL)sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo.After purification by flash column chromatography on silica gel(petroleum ether/ethyl acetate, 10:1, v/v), the desired product wasobtained as white solid (1.889 g, 69% yield). ¹H NMR (400 MHz, DMSO-d₆):δ 9.03 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.18-6.72 (m, 3H), 3.91 (s,3H).

Step 10:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide

To a solution of O-(2-(vinyloxy)ethyl)hydroxyl-amine (172 mg, 1.62 mmol)in THF (6 mL) was added LiHMDS (2.5 mL, 1 M in THF, 2.5 mmol) at −78° C.After stirring at this temperature for 10 min, a solution of methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate(360 mg, 0.81 mmol) in THF was syringed dropwisely. Then the mixture wasallowed to warm to ambient temperature, quenched with saturated NH₄Cl(aq., 20 mL) and extracted with ethyl acetate (15 mL×3). The combinedorganic extract was washed with water (10 mL×3) and brine (10 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. After purification byflash chromatography (petroleum ether/ethyl acetate, 10:1, v/v), thedesired product was obtained (410 mg, 98% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 11.85 (s, 1H), 8.98 (s, 1H), 8.04 (s, 1H), 7.89 (s, 1H),7.55 (d, J=10.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 6.53 (dd, J=13.9, 6.6Hz, 1H), 6.42 (d, J=6.0 Hz, 1H), 4.21 (d, J=14.5 Hz, 1H), 4.01 (m, 3H),3.83 (m, 2H).

Step 11:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide(410 mg, 0.8 mmol) in CH₂Cl₂ (5 mL) was added 1.0 N HCl (aq., 5 mL, 5mmol) dropwise. After stirring for 1 h, the reaction mixture wasneutralized with saturated NaHCO₃ (aq.). The organic layer wasseparated, washed with water (30 mL×2) and brine (30 mL) sequentially,dried over Na₂SO₄, filtered and concentrated in vacuo. The crude productwas purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 15:1,v/v) and the desired product was obtained as a white solid (290 mg, 52%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.83 (s, 1H), 8.92 (s, 1H), 8.03(s, 1H), 7.90 (s, 1H), 7.56 (d, J=9.4 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H),6.41 (m, 1H), 4.72 (m, 1H), 3.85 (m, 2H), 3.59 (m, 2H). MS (ES+): m/z492.35 [MH⁺].

Example 10 Preparation ofN-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide(Compound 10)

Step 1:N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylicacid (519 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (238 mg,1.62 mmol) was added. After stirring for 4 h at ambient temperature, thereaction was treated with saturated NH₄Cl (aq.). The resultant mixturewas extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts waswashed by water (30 mL) and brine (30 mL) sequentially, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product (475 mg)was used directly in the next step without further purification.

Step 2:N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide

To a solution ofN-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide(475 mg, 0.85 mmol) in CH₂Cl₂ (10 mL) was added trifluoroacetic acid(0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and neutralizedwith saturated sodium bicarbonate (aq.). The aqueous layer was extractedby CH₂Cl₂ (10 mL×2). The combined organic layers were washed by water(10 mL) and brine (10 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) to afford thedesired product (white solid, 310 mg, 45.4% yield for two steps). ¹H NMR(400 MHz, DMSO-d₆): δ 11.82 (s, 1H), 9.56 (s, 1H), 8.23 (s, 1H), 8.15(s, 1H), 7.57 (d, 1H), 7.32 (d, 1H), 6.47 (m, 1H), 4.85 (d, 1H), 4.62(m, 1H), 3.86 (m, 1H), 3.71 (m, 2H), 3.35 (m, 2H). MS APCI (+) m/z:522.5 [M+H].

Example 11 Preparation of5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide(Compound 11)

Step 1: 5-bromo-2,3,4-trifluorobenzoic acid

To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL)was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C.under nitrogen atmosphere. The stirring was maintained at thistemperature for 1 h. Then a solution of 1-bromo-2,3,4-trifluorobenzene(17.62 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 hat −78° C., the mixture was transferred to a bottle with dry ice. Themixture was stirred overnight at room temperature. The reaction wasquenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixturewas extracted with ethyl acetate (100 mL×3). The combined organicextracts were washed with water (100 mL) and brine (100 mL)sequentially, dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford the desired product (20.12 g, 94.5% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 13.95 (s, 1H), 7.97 (m, 1H).

Step 2: 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoic acid

To a solution of 2-chloroaniline (20.13 g, 157.80 mmol) and5-bromo-2,3,4-trifluorobenzoic acid (20.12 g, 78.90 mmol) in THF (120mL) was added LiHMDS (236.7 mL, 1 M in THF, 236.7 mmol) dropwisely at−78° C. under nitrogen atmosphere. The mixture was allowed to slowlywarm to room temperature and stirred at this temperature overnight. Thereaction was quenched with water (100 mL) and acidified to pH 2-3 with10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL×3).The combined organic extracts were washed with water (100 mL) and brine(100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated invacuo to afford the desired product (pale yellow solid, 25.63 g, 89.6%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 14.10 (s, 1H), 9.30 (s, 1H), 8.03(m, 1H), 7.47 (m, 1H), 7.23 (m, 1H), 7.04 (m, 2H).

Step 3: methyl 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoicacid (25.63 g, 70.69 mmol) in MeOH (300 mL) was added thionyl chloride(20 mL). The resulting solution was stirred at 85° C. overnight. MostMeOH was removed in vacuo. The residue was neutralized with saturatedsodium bicarbonate (aq.) and extracted with ethyl acetate (100 mL×3).The combined organic layer was washed with water (100 mL) and brine (100mL) sequentially, dried over Na₂SO₄, filtered and concentrated. Afterpurification by column chromatography on silica gel (petroleumether/ethyl acetate, 50:1, v/v), the corresponding product was obtainedas a white solid (22.84 g, 85.8% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.15(s, 1H), 8.06 (m, 1H), 7.41 (m, 1H), 7.24 (m, 1H), 7.00 (m, 1H), 6.91(m, 1H), 3.95 (s, 3H).

Step 4: methyl3,4-difluoro-2-((2-chlorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate

To a solution of methyl5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (22.84 g, 60.65mmol) in anhydrous 1,4-dioxane (200 mL) was addedN,N-diisopropylethylamine (15.68 g, 121.30 mmol). Then Pd₂(dba)₃ (2.78g, 3.03 mmol) followed by Xantphos (3.51 g, 6.06 mmol) and4-methoxy-α-toluenethiol (10.27 g, 66.72 mmol) was added under nitrogenatmosphere. The mixture was stirred overnight at 100° C. under N₂atmosphere and then allowed to warm to ambient temperature. Theinsoluble matter was filtered off and the filter cake was washed ethylacetate. The filtrate was diluted with water (300 mL) and extracted withethyl acetate (100 mL×3). The combined organic layers were washed withwater (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄,filtered and concentrated. The crude product was purified by columnchromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v)to give the desired product (pale yellow solid, 24.18 g, 88.6% yield).¹H NMR (400 MHz, CDCl₃): δ 9.14 (s, 1H), 7.77 (dd, 1H), 7.41 (dd, 1H),7.24 (m, 3H), 7.19 (m, 1H), 7.01 (m, 1H), 6.88 (m, 2H), 4.02 (s, 2H),3.92 (s, 3H), 3.81 (s, 3H).

Step 5: methyl4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of methyl5-(4-methoxybenzylthio)-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate(24.18 g, 53.75 mmol) in DMF (200 mL) was added NaN₃ (4.19 g, 64.49mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h.Then water (200 mL) was added. The solution was extracted with ethylacetate (100 mL×3). The combined organic extracts were washed with water(100 mL) and brine (100 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v)and gave the desired product (pale yellow solid, 21.63 g, 85.1% yield).¹H NMR (400 MHz, CDCl₃): δ 9.01 (s, 1H), 7.80 (s, 1H), 7.33 (m, 4H),7.15 (m, 1H), 6.90 (m, 1H), 6.85 (m, 2H), 4.05 (s, 2H), 3.92 (s, 3H),3.81 (s, 3H).

Step 6: methyl4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of methyl4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-chlorophenyl)amino)-benzoate(21.63 g, 45.74 mmol) in MeOH (500 mL) was added and 10% palladium oncarbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmospherewas completely changed to hydrogen atmosphere. The mixture was stirredfor 2 h at ambient temperature. After the insoluble matter was filteredoff, the solvent was evaporated in vacuo to give the desired product(19.93 g, 97.5% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.99 (s, 1H), 7.82(s, 1H), 7.21 (m, 1H), 7.17 (m, 3H), 6.87 (m, 3H), 6.69 (m, 1H), 4.63(s, 2H), 3.85 (s, 5H), 3.81 (s, 3H).

Step 7: dimethyl5,5′-disulfanediylbis(4-amino-3-fluoro-2-((2-chlorophenyl)amino)benzoate)

To a solution of methyl4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate(19.93 g, 44.6 mmol) in CH₂Cl₂ (180 mL) was added DDQ (11.25 g, 53.73mmol) followed by water (20 mL). After stirring at ambient temperaturefor 10 h, the reaction was quenched by saturated sodium bicarbonate(aq., 100 mL). The aqueous layer was extracted by CH₂Cl₂ (100 mL×3). Thecombined organic phase was washed with water (100 mL) and brine (100 mL)sequentially, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography on silica gel (petroleumether/ethyl acetate, 5:1, v/v) to give the desired product (pale yellowsolid, 9.39 g, 32.3% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.33 (s, 2H),7.46 (s, 2H), 7.40 (m, 2H), 7.15 (m, 2H), 6.92 (m, 2H), 6.76 (m, 2H),4.86 (br, 4H), 3.80 (s, 6H).

Step 8: methyl4-amino-3-fluoro-2-((2-chlorophenyl)amino)-5-mercaptobenzoate

To a solution of dimethyl5,5′-disulfanediylbis(4-amino-3-fluoro-2-((2-chlorophenyl)amino)benzoate)(9.39 g, 14.41 mmol) in THF/MeOH (100 mL, 10:1, v/v) was added NaBH₄(2.73 g, 72.05 mmol) portion-wise in 1 h. After stirring at ambienttemperature for 1 h, the reaction was quenched with 10% HCl (aq.) and pHwas adjusted to 1-2. The aqueous layer was extracted with CH₂Cl₂ (50mL×3). The combined organic phase was washed with water (50 mL) andbrine (50 mL) sequentially, dried over Na₂SO₄, filtered and concentratedin vacuo. The crude product was used directly in the next step withoutfurther purification.

Step 9: methyl4-fluoro-5-((2-chlorophenyl)amino)benzo[c]thiazole-6-carboxylate

To a solution of methyl4-amino-3-fluoro-2-((2-chlorophenyl)amino)-5-mercaptobenzoate intrimethyl orthoformate (50 mL) was added p-TsOH (0.58 g, 3.05 mmol). Thereaction mixture was stirred for 1 h and treated with water (100 mL).The precipitate was filtered off and the filter cake was washed withwater to afford the desired product (pale yellow solid, 8.50 g, 87.6%yield for two steps). ¹H NMR (400 MHz, CDCl₃): δ 9.13 (s, 1H), 8.70 (s,1H), 8.50 (s, 1H), 7.41 (m, 1H), 7.15 (m, 1H), 6.89 (m, 1H), 6.73 (m,1H), 3.93 (s, 3H).

Step 10: methyl4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[c]thiazole-6-carboxylate

To a solution of methyl4-fluoro-5-((2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylate (8.50g, 25.24 mmol) in DMF (100 mL) was added NBS (4.92 g, 27.76 mmol). Afterstirring for 5 h at ambient temperature, the reaction was treated bywater (150 mL). The precipitate was filtered off and the filter cake waswashed with water. The desired product was obtained as a pale brownsolid (8.74 g, 83.3% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.17 (s, 1H),8.70 (s, 1H), 8.48 (s, 1H), 7.65 (m, 1H), 7.30 (m, 1H), 6.63 (m, 1H),3.98 (s, 3H).

Step 11:4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylicacid

To a solution of methyl4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylate(8.74 g, 21.02 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 MLiOH (aq., 9.5 mL). After stirring at ambient temperature for 2 h, thereaction was treated with 10% HCl (aq.) till the solution was acidic.The aqueous layer was extracted with ethyl acetate (50 mL×3). Thecombined organic phase was washed with water (100 mL) and brine (100 mL)sequentially, dried over Na₂SO₄, filtered and concentrated to give thedesired product (8.08 g, 95.7% yield). ¹H NMR (400 MHz, DMSO-d₆): δ11.09 (s, 1H), 9.18 (s, 1H), 8.71 (s, 1H), 8.47 (s, 1H), 7.44 (m, 1H),7.31 (m, 1H), 6.65 (m, 1H).

Step 12:4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide

To a solution of4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylicacid (482 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h andO-(2-(vinyloxy)ethyl)hydroxyl-amine (172 mg, 1.62 mmol) was added. Afterstirring for 4 h at ambient temperature, the reaction was treated withsaturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂(30 mL×3). The combined organic extracts were washed with water (30 mL)and brine (30 mL), dried over Na₂SO₄ filtered, and concentrated invacuo. The crude product (503 mg) was used directly in the next stepwithout further purification.

Step 13:4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide

To a solution of4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide(503 mg, 1.03 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 5 mL, 5mmol). After stirring for 1 h, the reaction mixture was neutralized withsaturated NaHCO₃ (aq.). The aqueous layer was washed with CH₂Cl₂ (30mL). The combined organic layer was washed with water (30 mL×2) andbrine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The crude product was purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product as a white solid(420 mg, 75.9% yield for the two steps). ¹H NMR (400 MHz, DMSO-d₆): δ11.75 (s, 1H), 9.53 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.56 (d, m,1H), 7.33 (m, 1H), 6.50 (m, 1H), 4.75 (m, 1H), 3.83 (m, 2H), 3.58 (m,2H). MS: m/z 461.9, [M+H].

Example 12 Preparation ofN-(2,3-dihydroxypropoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxamide(Compound 12)

Step 1:N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-chloro-4-bromophenyl)amino)benzo[d]thiazole-6-carboxamide

To a solution of4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylicacid (482 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (238 mg,1.62 mmol) was added. After stirring for 4 h at ambient temperature, thereaction was treated with saturated NH₄Cl (aq.). The resultant mixturewas extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts waswashed by water (30 mL) and brine (30 mL) sequentially, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product (490 mg)was used directly in the next step without further purification.

Step 2:N-(2,3-dihydroxypropoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxamide

To a solution ofN-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxamide(490 mg, 0.92 mmol) in CH₂Cl₂ (10 mL) was added trifluoroacetic acid(0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and neutralizedwith saturated sodium bicarbonate (aq.). The aqueous layer was extractedby CH₂Cl₂ (10 mL×2). The combined organic layers were washed by water(10 mL) and brine (10 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) to afford thedesired product (white solid, 345 mg, 58.6% yield for two steps). ¹H NMR(400 MHz, DMSO-d₆): δ 11.80 (s, 1H), 9.54 (s, 1H), 8.24 (s, 1H), 8.18(s, 1H), 7.60 (d, 1H), 7.34 (d, 1H), 6.46 (m, 1H), 4.84 (d, 1H), 4.60(m, 1H), 3.88 (m, 1H), 3.74 (m, 2H), 3.36 (m, 2H). MS APCI (+) m/z:491.9 [M+H].

Example 13 Preparation ofN-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropanesulfonamide(Compound 13)

Step 1:4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylicacid (75 mg, 0.17 mmol) in t-BuOH (3 mL) was added DPPA (82 mg, 0.29mmol) followed by triethylamine (36 mg, 0.36 mmol). The mixture washeated under reflux for 3 h and allowed to slowly warm to roomtemperature. The solvent was removed in vacuo and the resultant crudeproduct was purified by column chromatography on silica gel (petroleumether/ethyl acetate, 2:1, v/v). The corresponding product was obtained(70 mg, 94.0% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.78 (s, 1H), 8.66(s, 1H), 7.95 (d, 1H), 7.74 (d, 1H), 7.47 (t, 1H), 7.33 (s, 1H).

Step 2:7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one

To a solution of4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one(70 mg, 0.16 mmol) in CH₂Cl₂ (5 mL) was added triethylamine (48 mg, 0.49mmol) at 0° C. followed by cyclopropanesulfonyl chloride (35 mg, 0.25mmol) and DMAP (10 mg). The mixture was stirred at room temperature for1 h and washed with saturated NaHCO₃ (aq.). The aqueous layer wasextracted with CH₂Cl₂ (10 mL×2). The combined organic phase was washedwith water (10 mL) and brine (10 mL) successively, dried over

Na₂SO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1,v/v) to give the corresponding product (80 mg, 92% yield). ¹H NMR (400MHz, CDCl₃): δ 8.68 (s, 1H), 7.98 (s, 1H), 7.91 (d, 1H), 7.76 (d, 1H),7.45 (t, 1H), 3.35 (m, 1H), 1.69 (m, 2H), 0.91 (m, 2H).

Step 3:N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropanesulfonamide

To a solution of7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one(50 mg, 0.09 mmol) in THF (5 mL) was added potassium trimethylsilanolate(19 mg, 0.14 mmol). After stirring at room temperature for 1 h, thereaction was quenched with saturated NH₄Cl (aq., 5 mL). The aqueouslayer was extracted with ethyl acetate (10 mL×2). The combined organicphase was washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residual crude product was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1,v/v) to give the corresponding product as a white solid (30 mg, 63.1%yield). ¹H NMR (400 MHz, CDCl₃): δ 8.65 (s, 1H), 8.02 (s, 1H), 7.91 (d,1H), 7.86 (s, 1H), 7.76 (d, 1H), 7.45 (m, 1H), 5.52 (s, 1H), 2.85 (m,1H), 1.29 (m, 2H), 1.20 (m, 2H). MS APCI (+) m/z: 508.5 [M+H].

Example 14 Preparation of1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide(Compound 14)

Step 1:7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one

To a solution of4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one(50 mg, 0.12 mmol) in DCM (5 mL) was added triethylamine (35 mg, 0.74mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (32mg, 0.18 mmol) and

DMAP (15 mg). After stirring at room temperature for 1 h, the mixturewas washed with saturated NaHCO₃ (aq.). The aqueous layer was extractedwith DCM (20 mL×2). The combined organic phase was washed by water (20mL) and brine (20 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated to give a residue, which was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v)to give the corresponding product (60 mg, 89.8% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.67 (s, 1H), 7.97 (s, 1H), 7.92 (d, 1H), 7.78 (d, 1H), 7.46(t, 1H), 5.76-5.60 (m, 1H), 5.06 (m, 2H), 2.91-2.81 (m, 1H), 2.11-2.01(m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).

Step 2:1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one(60 mg, 0.11 mmol) in THF (5 mL) was added potassium trimethylsilanolate(14 mg, 0.11 mmol). The reaction was stirred at room temperature for 1 hand quenched with saturated NH₄Cl (aq.). The aqueous layer was extractedwith EA (10 mL×2). The combined organic phase was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel (petroleumether/ethyl acetate, 5:1-3:1, v/v) to give the desired product (50 mg,91.3% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.67 (s, 1H), 7.97 (s, 1H),7.92 (d, 1H), 7.78 (d, 1H), 7.46 (m, 1H), 6.82 (s, 1H), 6.64 (s, 1H),5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.00 (m, 1H),1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).

Step 3:1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide(50 mg, 0.09 mmol) in THF (5 mL) was added N-methylmorpholine-N-oxide(11 mg, 0.09 mmol) followed by osmium tetraoxide (3 mg, 0.01 mmol) andwater (0.5 mL). The resultant was stirred at room temperature overnight.The mixture was concentrated and then diluted with ethyl acetate. Theorganic layer was washed with water, saturated NaHCO₃ (aq.) and brinesequentially, dried over Na₂SO₄, filtered and concentrated to give aresidue, which was purified by flash chromatography on silica gel togive the product as white solid (20 mg, 37.7% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.68 (s, 1H), 7.98 (s, 1H), 7.90 (d, 1H), 7.75 (d, 1H), 7.45(m, 1H), 6.81 (s, 1H), 6.66 (s, 1H), 4.42-4.28 (m, 2H), 4.21-4.12 (m,1H), 3.76-3.62 (m, 1H), 3.60-3.50 (m, 1H), 2.62-2.50 (m, 2H), 0.92-0.80(m, 4H). MS APCI (+) m/z: 582.5 [M+H].

Example 15 Preparation ofN-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)cyclopropanesulfonamide(Compound 15)

Step 1:5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one

To a solution of5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazole-6-carboxylicacid (120 mg, 0.299 mmol) in t-BuOH (10 mL) was added DPPA (48 mg, 0.449mmol) followed by triethylamine (60 mg, 0.598 mmol). The mixture washeated under reflux for 3 h and allowed to slowly warm to roomtemperature. The solvent was removed in vacuo and the resultant crudeproduct was purified by column chromatography on silica gel (petroleumether/ethyl acetate, 2:1, v/v). The corresponding product was obtained(white solid, 100 mg, 83.9% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.76(s, 1H), 8.65 (s, 1H), 7.95 (d, 1H), 7.77 (d, 1H), 7.50 (m, 1H), 7.39(s, 1H).

Step 2:5-(4-bromo-2-chlorophenyl)-7-(cyclopropylsulfonyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one

To a solution of5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one(100 mg, 0.25 mmol) in CH₂Cl₂ (10 mL) was added triethylamine (76 mg,0.75 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (53 mg,0.38 mmol) and DMAP (10 mg). The mixture was stirred at room temperaturefor 1 h and washed with saturated NaHCO₃ (aq.). The aqueous layer wasextracted with CH₂Cl₂ (15 mL×2). The combined organic phase was washedwith water (15 mL) and brine (20 mL) successively, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v)to give the corresponding product (120 mg, 95.1% yield). ¹H NMR (400MHz, CDCl₃): δ 8.67 (s, 1H), 7.99 (s, 1H), 7.91 (d, 1H), 7.73 (d, 1H),7.50 (m, 1H), 3.37 (m, 1H), 1.70 (m, 2H), 0.93 (m, 2H).

Step 3:N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)cyclopropanesulfonamide

To a solution of5-(4-bromo-2-chlorophenyl)-7-(cyclopropylsulfonyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one(50 mg, 0.10 mmol) in THF (5 mL) was added potassium trimethylsilanolate(13 mg, 0.10 mmol). After stirring at room temperature for 1 h, thereaction was quenched with saturated NH₄Cl (aq.). The aqueous layer wasextracted with ethyl acetate (10 mL×2). The combined organic phase waswashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedin vacuo. The residual crude product was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1,v/v) and the product was obtained (30 mg, 63.3% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.65 (s, 1H), 8.00 (s, 1H), 7.89 (d, 1H), 7.84 (s, 1H), 7.75(d, 1H), 7.43 (m, 1H), 5.48 (s, 1H), 2.84 (m, 1H), 1.29 (m, 2H), 1.23(m, 2H). MS APCI (+) m/z: 477.9, [M+H].

Example 16 Preparation ofN-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide(Compound 16)

Step 1:7-((1-allylcyclopropyl)sulfonyl)-5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-c]thiazol-6(7H)-one

To a solution of5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one(50 mg, 0.13 mmol) in DCM (10 mL) was added triethylamine (38 mg, 0.38mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (34mg, 0.19 mmol) and DMAP (10 mg). After stirring at room temperature for1 h, the reaction was treated with saturated NaHCO₃ (aq.). The aqueouslayer was extracted with CH₂Cl₂ (20 mL×2). The combined organic phasewas washed with water (20 mL) and brine (20 mL) sequentially, dried overNa₂SO₄, filtered and concentrated to give a residue, which was purifiedby flash chromatography on silica gel (petroleum ether/ethyl acetate,5:1, v/v) to give the corresponding product (62 mg, 91.1% yield). ¹H NMR(400 MHz, CDCl₃): δ 8.65 (s, 1H), 7.98 (s, 1H), 7.91 (d, 1H), 7.76 (d,1H), 7.48 (t, 1H), 5.76-5.63 (m, 1H), 5.08 (m, 2H), 2.90-2.83 (m, 1H),2.10-2.00 (m, 1H), 1.96-1.88 (m, 2H), 1.26-1.15 (m, 2H).

Step 2:1-allyl-N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of7-((1-allylcyclopropyl)sulfonyl)-5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one(60 mg, 0.111 mmol) in THF (5 mL) was added potassiumtrimethylsilanolate (15 mg, 0.111 mmol). The mixture was stirred at roomtemperature for 1 h and treated with saturated NH₄Cl (aq.). The aqueouslayer was extracted with ethyl acetate (10 mL×2). The combined organicphase was washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to give a residue, which was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1,v/v) to give the product as a white solid (50 mg, 87.5% yield). ¹H NMR(400 MHz, CDCl₃) δ 8.65 (s, 1H), 7.98 (s, 1H), 7.90 (d, 1H), 7.76 (d,1H), 7.45 (m, 1H), 6.80 (s, 1H), 6.63 (s, 1H), 5.75-5.60 (m, 1H), 5.03(m, 2H), 2.92-2.81 (m, 1H), 2.12-2.01 (m, 1H), 1.93-1.85 (m, 2H),1.20-1.11 (m, 2H).

Step 3:N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thia-zol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide

To a solution of1-allyl-N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide(50 mg, 0.10 mmol) in THF (10 mL) was added N-methylmorpholine-N-oxide(12 mg, 0.1 mmol) followed by osmium tetraoxide (5 mg, 0.02 mmol) andwater (0.5 mL). After stirring at room temperature overnight, themixture was concentrated and then diluted with EA. The organic layer waswashed with water, saturated NaHCO₃ (aq.) and brine sequentially, driedover Na₂SO₄, filtered and concentrated to give a residue, which waspurified by flash chromatography to give the product as white solid (25mg, 46.9% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 7.96 (s, 1H),7.92 (d, 1H), 7.73 (d, 1H), 7.44 (m, 1H), 6.82 (s, 1H), 6.68 (s, 1H),4.42-4.25 (m, 2H), 4.21-4.13 (m, 1H), 3.73-3.62 (m, 1H), 3.61-3.51 (m,1H), 2.63-2.52 (m, 2H), 0.91-0.83 (m, 4H). MS APCI (+) m/z: 551.9,[M+H].

Example 17 Preparation of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide(Compound 17)

Step 1: 5-bromo-2,3,4-trifluorobenzoic acid

To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL)was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C.under nitrogen atmosphere. The stirring was maintained at thistemperature for 1 h. Then a solution of 1-bromo-2,3,4-trifluorobenzene(17.62 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 hat −78° C., the mixture was transferred to a bottle with dry ice. Themixture was stirred overnight at room temperature. The reaction wasquenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixturewas extracted with ethyl acetate (100 mL×3). The combined organicextracts were washed with water (100 mL) and brine (100 mL)sequentially, dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford the desired product (20.12 g, 94.5% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 13.95 (s, 1H), 7.97 (m, 1H).

Step 2: 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (17.54 g, 157.80 mmol) and5-bromo-2,3,4-trifluorobenzoic acid (20.12 g, 78.90 mmol) in THF (120mL) was added LiHMDS (236.7 mL, 1 M in THF, 236.7 mmol) dropwisely at−78° C. under nitrogen atmosphere. The mixture was allowed to slowlywarm to room temperature and stirred at this temperature overnight. Thereaction was quenched with water (100 mL) and acidified to pH 2-3 with10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL×3).The combined organic extracts were washed with water (100 mL) and brine(100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated invacuo to afford the desired product (pale yellow solid, 24.24 g, 88.8%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.22 (s, 1H), 8.01 (dd, J=7.4, 2.1Hz, 1H), 7.25 (m, 1H), 7.10 (m, 3H).

Step 3: methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoicacid (24.24 g, 70.04 mmol) in MeOH (300 mL) was added thionyl chloride(20 mL). After stirring at 85° C. overnight, most MeOH was removed invacuo. The residue was neutralized with saturated sodium bicarbonate(aq.) and extracted with ethyl acetate (100 mL×3). The combined organiclayer was washed with water (100 mL) and brine (100 mL) sequentially,dried over Na₂SO₄, filtered and concentrated. After purification bycolumn chromatography on silica gel (petroleum ether/ethyl acetate,50:1, v/v), the corresponding product was obtained as a white solid(22.33 g, 88.5% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.06 (s, 1H), 8.01(dd, J=7.1, 2.3 Hz, 1H), 7.04 (m, 4H), 3.92 (s, 3H).

Step 4: methyl5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (22.33 g, 62.01mmol) in anhydrous 1,4-dioxane (200 mL) was addedN,N-diisopropylethylamine (16.03 g, 124.04 mmol). Then Pd₂(dba)₃ (2.84g, 3.10 mmol) followed by Xantphos (3.59 g, 6.20 mmol) and BnSH (8.09 g,65.11 mmol) was added under nitrogen atmosphere. The mixture was stirredovernight at 100° C. under N₂ atmosphere and then allowed to warm toambient temperature. The insoluble matter was filtered off and thefilter cake was washed ethyl acetate. The filtrate was diluted withwater (300 mL) and extracted with ethyl acetate (100 mL×3). The combinedorganic layers were washed with water (100 mL) and brine (100 mL)sequentially, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography on silica gel (petroleumether/ethyl acetate, 50:1, v/v) to give the desired product (pale yellowsolid, 22.09 g, 88.3% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.04 (s, 1H),7.68 (dd, 1H), 7.18 (m, 5H), 6.97 (m, 4H), 3.97 (s, 2H), 3.80 (s, 3H).

Step 5: methyl4-azido-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (22.09 g,54.76 mmol) in DMF (300 mL) was added NaN₃ (4.27 g, 65.71 mmol) atambient temperature. The mixture was stirred at 90° C. for 3 h. Thenwater (300 mL) was added. The solution was extracted with ethyl acetate(100 mL×3). The combined organic extracts were washed with water (100mL) and brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product(white solid, 19.43 g, 83.2% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.98 (s,1H), 7.75 (d, 1H), 7.27 (m, 5H), 7.02 (m, 4H), 4.07 (s, 2H), 3.89 (s,3H).

Step 6: methyl4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (19.43 g, 45.56 mmol) in MeOH (500 mL) was addedand 10% palladium on carbon (3.40 g) under nitrogen atmosphere. Then thenitrogen atmosphere was completely changed to hydrogen atmosphere. Themixture was stirred for 3 h at ambient temperature. After the insolublematter was filtered off, the solvent was evaporated in vacuo to give thedesired product (18.06 g, 99.0%). ¹H NMR (400 MHz, CDCl₃): δ 9.08 (s,1H), 7.78 (s, 1H), 7.11 (m, 9H), 4.65 (s, 2H), 3.88 (s, 2H), 3.84 (s,3H).

Step 7: methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (2.07g, 5.17 mmol) in acetic acid (60 mL) was added con. HCl (8 mL). Theresultant was stirred at ambient temperature for 1 h. A solution ofNaNO₂ (0.43 g, 6.21 mmol) in water (10 mL) was added dropwisely at 0° C.in 20 min. After stirring for 3 h, the reaction was treated withsaturated NaHCO₃ (aq.) till the solution was neutral. The aqueous layerwas extracted with ethyl acetate (30 mL×3). The combined organic phasewas washed with water (30 mL) and brine (30 mL) sequentially, dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography on silica gel (petroleum ether/ethyl acetate, 5:1,v/v) to give the corresponding product (yellow solid, 1.53 g, 92.1%yield). ¹H NMR (400 MHz, CDCl₃): δ 8.74 (s, 1H), 8.57 (s, 1H), 7.08 (m,4H), 4.03 (s, 3H).

Step 8: methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate(1.53 g, 4.77 mmol) in DMF (20 mL) was added NIS (1.18 g, 5.24 mmol)followed by trifluoroacetic acid (0.5 mL). After stirring for 5 h atambient temperature, the reaction was quenched by saturated NH₄Cl (aq.).The solution was extracted with ethyl acetate (30 mL×3). The combinedorganic extracts were washed with water (30 mL) and brine (30 mL)successively, dried over Na₂SO₄ and concentrated in vacuo to give thedesired product (yellow solid, 1.90 g, 89.1% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.73 (s, 1H), 8.58 (d, 1H), 7.47 (m, 1H), 7.39 (m, 1H), 6.74(m, 1H), 4.03 (s, 3H).

Step 9:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid

To a solution of methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate(1.90 g, 4.25 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 MLiOH (aq., 2 mL, 10 mmol). After stirring at ambient temperature for 2h, the reaction was treated with 1.0 M HCl (aq.) till the solution wasacidic. The aqueous layer was extracted with ethyl acetate (30 mL×3).The combined organic phase was washed with water (30 mL) and brine (30mL) sequentially, dried over Na₂SO₄, filtered and concentrated to givethe desired product (brown solid, 1.73 g, 94.0% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.87 (s, 1H), 8.84 (s, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 6.78(m, 1H).

Step 10:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid (200 mg, 0.49 mmol) in CH₂Cl₂ (10 mL) was added HOBt (100 mg, 0.69mmol) and EDCI (140 mg, 0.69 mmol). The mixture was stirred for 1 h andO-(2-(vinyl-oxy)ethyl)hydroxylamine (72 mg, 0.69 mmol) was added. Afterstirring for 4 h at ambient temperature, the reaction was treated withsaturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂(15 mL×3). The combined organic extracts were washed with water (10 mL)and brine (10 mL), dried over Na₂SO₄ filtered, and concentrated invacuo. The crude product was purified by column chromatography on silicagel (CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product (yellow solid,190 mg, 79.7% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.85 (s, 1H), 8.65(s, 1H), 8.51 (s, 1H), 7.38 (d, 1H), 7.29 (d, 1H), 6.64 (dd, 1H), 6.42(d, 1H), 4.21 (d, 1H), 4.01 (m, 3H), 3.83 (m, 2H).

Step 11:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide(190 mg, 0.37 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 1.5 mL,1.5 mmol). After stirring for 1 h, the reaction mixture was neutralizedwith saturated NaHCO₃ (aq.). The aqueous layer was washed with CH₂Cl₂(10 mL×2). The combined organic layer was washed with water (30 mL) andbrine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The crude product was purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 20:1, v/v) and gave the desired product as a yellow solid(154 mg, 84.6% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.88 (s, 1H), 8.65(s, 1H), 8.52 (s, 1H), 7.36 (d, 1H), 7.25 (d, 1H), 6.42 (d, 1H), 4.69(m, 1H), 4.05 (m, 2H), 3.80 (m, 2H). MS APCI (+) m/z: m/z 493.2, [M+H].

Example 17A Preparation of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide(Compound 17)

Step 1: 5-bromo-2,3,4-trifluorobenzoic acid

To a solution of 1-bromo-2,3,4-trifluorobenzene (13.64 g, 64.6 mmol) inTHF (120 mL) was added lithium diisopropylamide (2.0 M in THF, 33.9 mL,67.8 mmol) at −78° C. under nitrogen atmosphere. After stirring for 1 hat −78° C., the mixture was transferred to a bottle with dry ice. Themixture was stirred overnight at room temperature. The reaction wasquenched with 10% aqueous HCl (300 mL) and extracted with ethyl acetate(200 mL×3). The combined organic extracts were washed with 5% sodiumhydroxide (300 mL). The aqueous layer was acidized to pH 1 and extractedwith ethyl acetate (200 mL×3). The combined organic extract was driedover Na₂SO₄, filtered and concentrated under reduced pressure to affordthe desired product (white solid, 13.51 g, 82% yield). ¹H NMR (400 MHz,CDCl₃): δ 13.94 (s, 1H), 7.95 (m, 1H).

Step 2: 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (10.2 mL, 105.8 mmol) and5-bromo-2,3,4-trifluorobenzoic acid (13.51 g, 52.9 mmol) in THF (120 mL)was added LiHMDS (158.7 mL, 1 M in THF, 158.7 mmol) dropwisely at −78°C. under nitrogen atmosphere. The mixture was allowed to slowly warm toroom temperature and stirred at this temperature overnight. The reactionwas quenched with 10% HCl (aq., 100 mL) and extracted with ethyl acetate(200 mL×3). The combined organic extracts were washed with water (200mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated in vacuo to afford the desired product (pale yellow solid,13.73 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.21 (s, 1H), 8.01 (d,1H), 7.26 (m, 1H), 7.01-7.16 (m, 3H).

Step 3: methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoicacid (13.73 g, 39.6 mmol) in MeOH (300 mL) was added SOCl₂ (60 mL).After stirring at 85° C. overnight, most MeOH was removed in vacuo. Theresidue was neutralized with saturated sodium bicarbonate (aq.) andextracted with ethyl acetate (300 mL×3). The combined organic extractwas washed with water (200 mL×3) and brine (200 mL) sequentially, driedover Na₂SO₄, filtered and concentrated in vacuo to afford thecorresponding product (gray solid, 12.58 g, 90% yield). ¹H NMR (400 MHz,CDCl₃): δ 9.09 (s, 1H), 8.05 (d, 1H), 7.00-7.14 (m, 4H), 3.94 (s, 3H).

Step 4: methyl5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.85 g, 35.80mmol) in anhydrous 1,4-dioxane (30 mL) was addedN,N-diisopropylethylamine (9.21 g, 71.60 mmol). Then Pd₂(dba)₃ (1.63 g,1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and BnSH (4.44 g,35.80 mmol) was added under nitrogen atmosphere. The mixture was stirredovernight at 100° C. under N₂ atmosphere. Then the reaction was allowedto warm to ambient temperature and quenched with water (150 mL). Theaqueous layer was extracted with ethyl acetate (200 mL×3). The combinedorganic layers were washed with water (200 mL×3) and brine (200 mL)sequentially, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography on silica gel (petroleumether/ethyl acetate, 50:1, v/v) to give the desired product (whitesolid, 12.64 g, 88% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 7.68(dd, J=7.5, 2.1 Hz, 1H), 7.21-7.14 (m, 5H), 7.05-6.89 (m, 4H), 3.97 (s,2H), 3.80 (s, 3H).

Step 5: methyl4-azido-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.64 g,31.36 mmol) in DMF (30 mL) was added NaN₃ (2.45 g, 37.63 mmol) atambient temperature. The mixture was stirred at 90° C. for 3 h. Thenwater (150 mL) was added. The solution was extracted with ethyl acetate(100 mL×3). The combined organic extracts were washed with water (100mL×3) and brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product(white solid, 10.38 g, 78% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.89 (s,1H), 7.66 (s, 1H), 7.27-7.12 (m, 3H), 7.10-6.80 (m, 6H), 3.98 (s, 2H),3.80 (s, 3H).

Step 6: methyl4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl4-azido-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (10.38g, 24.36 mmol) in MeOH (100 mL) was added and 10% palladium on carbon(1.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere wascompletely changed to hydrogen atmosphere. The mixture was stirred for 6h at ambient temperature. After the insoluble matter was filtered off,the solvent was evaporated in vacuo to give the desired product (9.79 g,100% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 7.69 (s, 1H),7.19-7.17 (m, 3H), 7.15-6.83 (m, 6H), 4.54 (s, 2H), 3.79 (s, 2H), 3.75(s, 3H).

Step 7: methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl4-amino-5-(benzylthio)-3-fluoro-2-((2-fluoro-phenyl)amino)benzoate (2.07g, 5.17 mmol) in acetic acid (60 mL) was added HCl (con., 8 mL) andwater (6 mL). The resultant was stirred at ambient temperature for 1 h.A solution of NaNO₂ (0.43 g, 6.21 mmol) in water (10 mL) was addeddropwisely at 0° C. within 20 min. After stirring for 3 h, the reactionwas treated with saturated NaHCO₃ (aq.) till the solution was neutral.The aqueous layer was extracted with ethyl acetate (30 mL×3). Thecombined organic extract was washed with water (30 mL×3) and brine (30mL) sequentially, dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by column chromatography on silica gel(petroleum ether/ethyl acetate, 5:1, v/v) to give the correspondingproduct (yellow solid, 1.53 g, 92.1% yield). ¹H NMR (400 MHz, CDCl₃): δ8.65 (s, 1H), 8.48 (s, 1H), 7.00-6.90 (m, 4H), 3.94 (s, 3H).

Step 8: methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate(1.53 g, 4.77 mmol) in DMF (10 mL) was added NIS (1.18 g, 5.24 mmol)followed by trifluoroacetic acid (0.5 mL). After stirring for 4 h atambient temperature, the reaction was quenched with saturated NH₄Cl(aq.). The solution was extracted with ethyl acetate (30 mL×3). Thecombined organic extracts were washed with water (30 mL×3) and brine (30mL) successively, dried over Na₂SO₄ and concentrated in vacuo to givethe desired product (yellow solid, 1.90 g, 89% yield). ¹H NMR (400 MHz,CDCl₃) δ 8.63 (s, 1H), 8.49 (s, 1H), 7.38 (d, J=10.3 Hz, 1H), 7.29 (d,J=8.6 Hz, 1H), 6.64 (dd, J=14.3, 8.3 Hz, 1H), 3.94 (s, 3H).

Step 9:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid

To a solution of methyl4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate(1.90 g, 4.25 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 1.0 MLiOH (aq., 10 mL, 10 mmol). After stirring at ambient temperature for 2h, the reaction was treated with 1.0 M HCl (aq.) till the solution wasacidic. The aqueous layer was extracted with ethyl acetate (30 mL×3).The combined organic phase was washed with water (30 mL×3) and brine (30mL) sequentially, dried over Na₂SO₄, filtered and concentrated to givethe desired product (brown solid, 1.70 g, 94.0% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.63 (s, 1H), 8.49 (s, 1H), 7.38 (d, J=10.3 Hz, 1H), 7.29 (d,J=8.6 Hz, 1H), 6.64 (dd, J=14.3, 8.3 Hz, 1H).

Step 10:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid (1.7 g, 5.54 mmol) in CH₂Cl₂ (20 mL) was added HOBt (1.21 g, 8.31mmol) and EDCI (1.59 mg, 8.31 mmol). The mixture was stirred for 1 h andO-(2-(vinyl-oxy)ethyl)hydroxylamine (0.69 g, 6.65 mmol) was added. Afterstirring for 4 h at ambient temperature, the reaction was treated withsaturated NH₄Cl (aq., 20 mL). The resultant mixture was extracted withCH₂Cl₂ (15 mL×3). The combined organic extracts were washed with water(10 mL×3) and brine (10 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) and gave thedesired product (2.44 g, 85% yield). ¹H NMR (400 MHz, d6-DMSO) δ 11.85(s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 7.38 (d, J=10.8 Hz, 1H), 7.29 (d,J=8.1 Hz, 1H), 6.64 (dd, J=13.9, 6.6 Hz, 1H), 6.42 (d, J=6.0 Hz, 1H),4.21 (d, J=14.5 Hz, 1H), 4.01 (m, 3H), 3.83 (m, 2H).

Step 11:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide(410 mg, 0.79 mmol) in CH₂Cl₂ (5 mL) was added 1.0 N HCl (aq., 5 mL, 5mmol). After stirring for 1 h, the reaction mixture was neutralized withsaturated NaHCO₃ (aq.). The organic layer was separated, washed withwater (30 mL×2) and brine (30 mL) sequentially, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) and gavethe desired product (343 mg, 88% yield). ¹H NMR (400 MHz, d6-DMSO) δ11.85 (s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 7.38 (d, J=10.8 Hz, 1H), 7.29(d, J=8.1 Hz, 1H), 6.64 (dd, J=13.9, 6.6 Hz, 1H), 4.21 (d, J=14.5 Hz,1H), 4.01 (m, 2H), 3.83 (m, 2H). MS (ES+): m/z 493.0 [M+H].

Example 18 Preparation ofN-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide(Compound 18)

Step 1:N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid (210 mg, 0.48 mmol) in CH₂Cl₂ (10 mL) was added HOBt (105 mg, 0.72mmol) followed by EDCI (138 mg, 0.72 mmol). The mixture was stirred for1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (108 mg,0.74 mmol) was added. After stirring for 4 h at ambient temperature, thereaction was treated with saturated NH₄Cl (aq.). The resultant mixturewas extracted with CH₂Cl₂ (15 mL×3). The combined organic extracts waswashed by water (10 mL) and brine (10 mL) sequentially, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product (229 mg)was used directly in the next step without further purification.

Step 2:N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution ofN-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide(229 mg, 0.41 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 1.5 mL,1.5 mmol). The mixture was stirred for 1 h and neutralized withsaturated sodium bicarbonate (aq.). The aqueous layer was extracted byCH₂Cl₂ (10 mL×2). The combined organic layers were washed by water (30mL×2) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) to afford thedesired product (yellow solid, 170 mg, 67.9% yield for two steps). ¹HNMR (400 MHz, DMSO-d₆): δ 11.98 (s, 1H), 8.40 (s, 1H), 8.20 (s, 1H),7.58 (d, 1H), 7.33 (d, 1H), 6.64 (m, 1H), 4.86 (m, 1H), 4.62 (m, 1H),3.87 (m, 1H), 3.72 (m, 2H), 3.33 (m, 2H, covered by the peak of water).MS APCI (+) m/z: 522.9 [M+H].

Example 19 Preparation of5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide(Compound 19)

Step 1: 5-bromo-2-((2-chlorophenyl)amino)-3,4-difluorobenzoic acid

To a solution of 2-chloroaniline (12.56 g, 98.42 mmol) and5-bromo-2,3,4-trifluorobenzoic acid (12.55 g, 49.21 mmol) in THF (120mL) was added LiHMDS (147.6 mL, 1 M in THF, 147.6 mmol) dropwisely at−78° C. under nitrogen atmosphere. The mixture was allowed to slowlywarm to room temperature and stirred at this temperature overnight. Thereaction was quenched with 10% HCl (aq., 100 mL). The mixture wasextracted with ethyl acetate (100 mL×3). The combined organic extractswere washed with water (100 mL) and brine (100 mL) sequentially, driedover Na₂SO₄, filtered and concentrated in vacuo to afford the desiredproduct 4 (yellow solid, 13.74 g, 77% yield). ¹H NMR (400 MHz, DMSO-d₆):δ 14.10 (s, 1H), 9.30 (s, 1H), 8.03 (m, 1H), 7.47 (m, 1H), 7.23 (m, 1H),7.04 (m, 2H).

Step 2: methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoicacid (13.74 g, 37.89 mmol) in MeOH (300 mL) was added thionyl chloride(20 mL). After stirring at 85° C. overnight, most MeOH was removed invacuo. The residue was neutralized with saturated sodium bicarbonate(aq.) and extracted with ethyl acetate (100 mL×3). The combined organiclayer was washed with water (100 mL) and brine (100 mL) sequentially,dried over Na₂SO₄, filtered and concentrated to give the correspondingproduct as a gray white solid (12.98 g, 91.1% yield). ¹H NMR (400 MHz,CDCl₃): δ 9.15 (s, 1H), 8.06 (m, 1H), 7.41 (m, 1H), 7.24 (m, 1H), 7.01(m, 1H), 6.90 (m, 1H), 3.95 (s, 3H).

Step 3: methyl5-(benzylthio)-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of methyl5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (12.98 g, 34.47mmol) in anhydrous 1,4-dioxane (30 mL) was addedN,N-diisopropylethylamine (8.86 g, 68.94 mmol). Then Pd₂(dba)₃ (1.63 g,1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and BnSH (4.48 g,36.19 mmol) was added under nitrogen atmosphere. The mixture was stirredovernight at 100° C. under N₂ atmosphere and then allowed to warm toambient temperature. The reaction was quenched with water (150 mL) andextracted with ethyl acetate (100 mL×3). The combined organic layerswere washed with water (100 mL) and brine (100 mL) sequentially, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby column chromatography on silica gel (petroleum ether/ethyl acetate,50:1, v/v) to give the desired product (white solid, 12.44 g, 86.0%yield). ¹H NMR (400 MHz, CDCl₃): δ 9.19 (s, 1H), 7.79 (dd, 1H), 7.41(dd, 1H), 7.24 (m, 5H), 7.18 (m, 1H), 7.00 (m, 1H), 6.87 (m, 1H), 4.08(s, 2H), 3.90 (s, 3H).

Step 4: methyl4-azido-5-(benzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of methyl5-(benzylthio)-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (12.44 g,29.64 mmol) in DMF (100 mL) was added NaN₃ (2.89 g, 44.46 mmol) atambient temperature. The mixture was stirred at 90° C. for 3 h. Thenwater (150 mL) was added. The solution was extracted with ethyl acetate(100 mL×3). The combined organic extracts were washed with water (100mL) and brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product(white solid, 9.84 g, 75.1% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.72(s, 1H), 7.65 (s, 1H), 7.45 (m, 1H), 7.33 (m, 4H), 7.24 (m, 2H), 6.95(m, 2H), 4.20 (s, 2H), 3.81 (s, 3H).

Step 5: methyl4-amino-5-(benzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of methyl4-azido-5-(benzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate (9.84g, 22.23 mmol) in MeOH (200 mL) was added and 10% palladium on carbon(1.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere wascompletely changed to hydrogen atmosphere. The mixture was stirred for 2h at ambient temperature. After the insoluble matter was filtered off,the solvent was evaporated in vacuo to give the desired product (9.26 g,100%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (s, 1H), 7.54 (s, 1H), 7.45 (m,1H), 7.24 (m, 6H), 6.95 (m, 1H), 6.77 (m, 1H), 6.27 (s, 2H), 3.95 (s,2H), 3.73 (s, 3H).

Step 6: methyl4-fluoro-5-((2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl4-amino-5-(benzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate (2.50g, 5.99 mmol) in acetic acid (60 mL) was added con. HCl (8 mL). Theresultant was stirred at ambient temperature for 1 h. A solution ofNaNO₂ (0.45 g, 6.58 mmol) in water (10 mL) was added dropwisely at 0° C.in 20 min. After stirring for 3 h, the reaction was treated withsaturated NaHCO₃ (aq.) till the solution was neutral. The aqueous layerwas extracted with ethyl acetate (30 mL×3). The combined organic phasewas washed with water (30 mL) and brine (30 mL) sequentially, dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography on silica gel (petroleum ether/ethyl acetate, 5:1,v/v) to give the corresponding product (yellow solid, 1.82 g, 90.1%yield). ¹H NMR (400 MHz, CDCl₃): δ 8.83 (s, 1H), 8.59 (d, 1H), 7.45 (m,1H), 7.24 (m, 1H), 6.95 (m, 2H), 4.03 (s, 3H).

Step 7: methyl4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl4-fluoro-5-((2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate(1.82 g, 5.39 mmol) in DMF (10 mL) was added NBS (1.0 g, 5.65 mmol).After stirring for 4 h at ambient temperature, the reaction was quenchedby saturated NH₄Cl (aq.). The solution was extracted with ethyl acetate(30 mL×3). The combined organic extracts were washed with water (30 mL)and brine (30 mL) successively, dried over Na₂SO₄ and concentrated invacuo to give the desired product (yellow solid, 2.02 g, 90.1% yield).¹H NMR (400 MHz, CDCl₃): δ 8.84 (s, 1H), 8.60 (d, 1H), 7.59 (d, 1H),7.29 (m, 1H), 6.77 (m, 1H), 4.04 (s, 3H).

Step 8:4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid

To a solution of methyl4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate(2.02 g, 4.85 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 MLiOH (aq., 2 mL, 10 mmol). After stirring at ambient temperature for 2h, the reaction was treated with 1.0 M HCl (aq.) till the solution wasacidic.

The aqueous layer was extracted with ethyl acetate (30 mL×3). Thecombined organic phase was washed with water (30 mL) and brine (30 mL)sequentially, dried over Na₂SO₄, filtered and concentrated to give thedesired product (brown yellow solid, 1.85 g, 95% yield). ¹H NMR (400MHz, CDCl₃): δ 13.90 (s, 1H), 8.80 (s, 1H), 8.55 (d, 1H), 7.56 (d, 1H),7.27 (m, 1H), 6.75 (m, 1H).

Step 9:4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid (200 mg, 0.46 mmol) in CH₂Cl₂ (10 mL) was added HOBt (100 mg, 0.74mmol) and EDCI (132 mg, 0.74 mmol). The mixture was stirred for 1 h andO-(2-(vinyloxy)ethyl)hydroxylamine (76 mg, 0.74 mmol) was added. Afterstirring for 4 h at ambient temperature, the reaction was treated withsaturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂(15 mL×3). The combined organic extracts were washed with water (10 mL)and brine (10 mL), dried over Na₂SO₄ filtered, and concentrated invacuo. The crude product (191 mg) was used directly in the next stepwithout further purification.

Step 10:4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of compound4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide(191 mg, 0.39 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 1.5 mL,1.5 mmol). After stirring for 1 h, the reaction mixture was neutralizedwith saturated NaHCO₃ (aq.). The aqueous layer was washed with CH₂Cl₂(10 mL×2). The combined organic layer was washed with water (30 mL×2)and brine (30 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by column chromatography on silicagel (CH₂Cl₂/MeOH, 20:1, v/v) and gave the desired product as a yellowsolid (150 mg, 66.5% yield for two steps). ¹H NMR (400 MHz, CD₃OD): δ8.53 (s, 1H), 7.69 (s, 1H), 7.34 (d, 1H), 6.74 (m, 1H), 3.91 (m, 2H),3.62 (m, 2H). MS APCI (+) m/z: 462.5 [M+H].

Example 20 Preparation of5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d][1,2,3]thiadiazole-6-carboxamide(Compound 20)

Step 1:N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-chloro-4-bromophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid (200 mg, 0.49 mmol) in CH₂Cl₂ (10 mL) was added HOBt (100 mg, 0.74mmol) followed by EDCI (140 mg, 0.74 mmol). The mixture was stirred for1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (108 mg,0.74 mmol) was added. After stirring for 4 h at ambient temperature, thereaction was treated with saturated NH₄Cl (aq.). The resultant mixturewas extracted with CH₂Cl₂ (15 mL×3). The combined organic extracts waswashed by water (10 mL) and brine (10 mL) sequentially, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product (213 mg)was used directly in the next step without further purification.

Step 2:N-(2,3-dihydroxypropoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution ofN-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide(60 mg, 0.11 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 1 mL, 1.0mmol). The mixture was stirred for 1 h and neutralized with saturatedsodium bicarbonate (aq.). The aqueous layer was extracted by CH₂Cl₂ (10mL×2). The combined organic layers were washed by water (10 mL) andbrine (10 mL) sequentially, dried over Na₂SO₄, filtered and concentratedin vacuo. The crude product was purified by column chromatography onsilica gel (CH₂Cl₂/MeOH, 20:1, v/v) to afford the desired product(yellow solid, 41 mg, 61.5% yield for two steps). ¹H NMR (400 MHz,CD₃OD): δ 11.13 (s, 1H), 8.59 (s, 1H), 7.66 (d, 1H), 7.34 (dd, 1H), 6.76(m, 1H), 3.79 (m, 1H), 3.71 (m, 2H), 3.35 (m, 2H). MS APCI (+) m/z: m/z492.8, [M+H].

Example 21 Preparation ofN-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide(Compound 21)

Step 1:4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one

To a solution of4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid (120 mg, 0.30 mmol) in t-BuOH (10 mL) was added DPPA (48 mg, 0.45mmol) followed by triethylamine (60 mg, 0.60 mmol). The mixture washeated under reflux for 3 h and allowed to slowly warm to roomtemperature. The solvent was removed in vacuo and the resultant crudeproduct was purified by column chromatography on silica gel (petroleumether/ethyl acetate, 2:1, v/v). The corresponding product was obtained(100 mg, 83.9% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (s, 1H),8.01-7.99 (m, 1H), 7.89 (s, 1H), 7.83 (m, 1H), 7.59-7.55 (m, 1H).

Step 2:7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one

To a solution of4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one(60 mg, 0.14 mmol) in CH₂Cl₂ (3 mL) was added triethylamine (43 mg, 0.42mmol) at 0° C. followed by cyclopropanesulfonyl chloride (31 mg, 0.21mmol) and DMAP (5 mg). The mixture was stirred at room temperature for 1h and washed with saturated NaHCO₃ (aq.). The aqueous layer wasextracted with CH₂Cl₂ (10 mL×2). The combined organic phase was washedwith water (10 mL) and brine (10 mL) successively, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v)to give the corresponding product (75 mg, 100% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.34 (s, 1H), 7.75-7.73 (d, 2H), 7.34 (m, 1H), 3.34 (m, 1H),1.68 (m, 2H), 0.85 (m, 2H).

Step 3:N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide

To a solution of7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one(70 mg, 0.13 mmol) in THF (5 mL) was added potassium trimethylsilanolate(17 mg, 0.13 mmol). After stirring at room temperature for 1 h, thereaction was quenched with saturated NH₄Cl (aq.). The aqueous layer wasextracted with ethyl acetate (6 mL×2). The combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedin vacuo. The residual crude product was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1,v/v) to give the corresponding product (40 mg, 60.1% yield). ¹H NMR (400MHz, DMSO-d₆): δ 9.86 (s, 1H), 8.37 (s, 1H), 7.73 (s, 1H), 7.60 (dd,1H), 7.30 (dd, 1H), 6.45 (m, 1H), 2.77 (m, 1H), 1.01-0.99 (m, 2H),0.89-0.86 (m, 2H). MS APCI (+) m/z: 508.7, [M+H].

Example 22 Preparation of1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide(Compound 22)

Step 1:7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one

To a solution of4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one(50 mg, 0.12 mmol) in DCM (5 mL) was added triethylamine (24 mg, 0.23mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (32mg, 0.17 mmol) and DMAP (10 mg). After stirring at room temperature for1 h, the mixture was washed with saturated NaHCO₃ (aq.). The aqueouslayer was extracted with DCM (20 mL×2). The combined organic phase waswashed by water (20 mL) and brine (20 mL) sequentially, dried overNa₂SO₄, filtered and concentrated to give a residue, which was purifiedby flash chromatography on silica gel (petroleum ether/ethyl acetate,5:1, v/v) to give the corresponding product (60 mg, 89.9% yield). ¹H NMR(400 MHz, CDCl₃): δ 8.36 (s, 1H), 7.76-7.74 (m, 2H), 7.35 (m, 1H),5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H),1.95-1.86 (m, 2H), 1.25-1.11 (m, 2H).

Step 2: 1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2, 3]thiadiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one(60 mg, 0.11 mmol) in THF (5 mL) was added potassium trimethylsilanolate(14 mg, 0.11 mmol). The reaction was stirred at room temperature for 1 hand quenched with saturated NH₄Cl (aq.). The aqueous layer was extractedwith EA (10 mL×2). The combined organic phase was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel (petroleumether/ethyl acetate, 5:1-3:1, v/v) to give the desired product (50 mg,87.3% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.24 (s, 1H), 7.65-7.63 (m,2H), 7.31 (m, 1H), 7.01 (s, 1H), 6.83 (s, 1H), 5.74-5.56 (m, 1H), 5.02(m, 2H), 2.77-2.71 (m, 1H), 2.12-2.0 (m, 1H), 1.75-1.71 (m, 2H),1.21-0.97 (m, 2H).

Step 3:1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide(50 mg, 0.09 mmol) in THF (5 mL) was added N-methylmorpholine-N-oxide(12 mg, 0.09 mmol) followed by osmium tetraoxide (5 mg, 0.02 mmol) andwater (0.5 mL). The resultant was stirred at room temperature overnight.The mixture was concentrated and then diluted with ethyl acetate. Theorganic layer was washed with water, saturated NaHCO₃ (aq.) and brinesequentially, dried over Na₂SO₄, filtered and concentrated to give aresidue, which was purified by flash chromatography on silica gel togive the product as white solid (30 mg, 56.5% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.26 (s, 1H), 7.67-7.64 (d, 2H), 7.32 (m, 1H), 7.03 (s, 1H),6.85 (s, 1H), 4.40-4.26 (m, 2H), 4.20-4.10 (m, 1H), 3.75-3.60 (m, 1H),3.60-3.50 (m, 1H), 2.62-2.50 (m, 2H), 0.92-0.82 (m, 4H).MS APCI (+) m/z:583.5, [M+H].

Example 23 Preparation ofN-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide(Compound 23)

Step 1:4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one

To a solution of4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylicacid (100 mg, 0.25 mmol) in t-BuOH (5 mL) was added DPPA (103 mg, 0.37mmol) followed by triethylamine (76 mg, 0.75 mmol). The mixture washeated under reflux for 3 h and allowed to slowly warm to roomtemperature. The solvent was removed in vacuo and the resultant crudeproduct was purified by column chromatography on silica gel (petroleumether/ethyl acetate, 2:1, v/v). The corresponding product was obtained(90 mg, 90.7% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.75 (s, 1H), 8.67(s, 1H), 7.96 (d, 1H), 7.76 (d, 1H), 7.50 (t, 1H).

Step 2:7-(cyclopropylsulfonyl)-4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one

To a solution of4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one(50 mg, 0.13 mmol) in CH₂Cl₂ (5 mL) was added triethylamine (26 mg, 0.25mmol) at 0° C. followed by cyclopropanesulfonyl chloride (26 mg, 0.19mmol) and DMAP (10 mg). The mixture was stirred at room temperature for1 h and washed with saturated NaHCO₃ (aq.). The aqueous layer wasextracted with CH₂Cl₂ (10 mL×2). The combined organic phase was washedwith water (10 mL) and brine (10 mL) successively, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v)to give the corresponding product (60 mg, 95% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.31 (s, 1H), 7.75-7.72 (d, 2H), 7.35 (m, 1H), 3.35 (m, 1H),1.70 (m, 2H), 0.87 (m, 2H).

Step 3:N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide

To a solution of7-(cyclopropylsulfonyl)-4-fluoro-5-(2-chloro-4-bromophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one(60 mg, 0.12 mmol) in THF (5 mL) was added potassium trimethylsilanolate(16 mg, 0.12 mmol). After stirring at room temperature for 1 h, thereaction was quenched with saturated NH₄Cl (aq.). The aqueous layer wasextracted with ethyl acetate (10 mL×2). The combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedin vacuo. The residual crude product was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1,v/v) to give the corresponding product (30 mg, 52.7% yield). ¹H NMR (400MHz, CDCl₃): δ 8.25 (s, 1H), 8.02-7.98 (m, 1H), 7.85 (m, 1H), 7.60-7.56(m, 1H), 7.14 (s, 1H), 6.83 (s, 1H), 2.81-2.72 (m, 1H), 1.33 (m, 2H),1.15 (m, 2H). MS APCI (+) m/z: 478.8, [M+H].

Example 24 Preparation ofN-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d][1,2,3]thiadiazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide(Compound 24)

Step 1:7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2, 3]thiadiazol-6(7H)-one

To a solution of4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one(40 mg, 0.10 mmol) in DCM (5 mL) was added triethylamine (21 mg, 0.20mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (27mg, 0.15 mmol) and DMAP (10 mg). After stirring at room temperature for1 h, the mixture was washed with saturated NaHCO₃ (aq.). The aqueouslayer was extracted with DCM (20 mL×2). The combined organic phase waswashed by water (20 mL) and brine (20 mL) sequentially, dried overNa₂SO₄, filtered and concentrated to give a residue, which was purifiedby flash chromatography on silica gel (petroleum ether/ethyl acetate,5:1, v/v) to give the corresponding product (50 mg, 87.1% yield). ¹H NMR(400 MHz, CDCl₃): δ 8.37 (s, 1H), 7.78-7.76 (d, 2H), 7.33 (m, 1H),5.76-5.58 (m, 1H), 5.08 (m, 2H), 2.93-2.86 (m, 1H), 2.13-2.0 (m, 1H),1.97-1.87 (m, 2H), 1.28-1.16 (m, 2H).

Step 2:1-allyl-N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-chloro-4-bromophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one(50 mg, 0.09 mmol) in THF (5 mL) was added potassium trimethylsilanolate(12 mg, 0.09 mmol). The reaction was stirred at room temperature for 1 hand quenched with saturated NH₄Cl (aq.). The aqueous layer was extractedwith EA (10 mL×2). The combined organic phase was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel (petroleumether/ethyl acetate, 5:1-3:1, v/v) to give the desired product (45 mg,94.5% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.26 (s, 1H), 7.65-7.57 (m,2H), 7.33 (m, 1H), 7.00 (s, 1H), 6.85 (s, 1H), 5.72-5.57 (m, 1H), 5.05(m, 2H), 2.79-2.72 (m, 1H), 2.12-2.05 (m, 1H), 1.76-1.71 (m, 2H),1.21-0.98 (m, 2H).

Step 3:1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of1-allyl-N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide(45 mg, 0.09 mmol) in THF (5 mL) was added N-methylmorpholine-N-oxide(10 mg, 0.09 mmol) followed by osmium tetraoxide (5 mg, 0.02 mmol) andwater (0.5 mL). The resultant was stirred at room temperature overnight.The mixture was concentrated and then diluted with ethyl acetate. Theorganic layer was washed with water, saturated NaHCO₃ (aq.) and brinesequentially, dried over Na₂SO₄, filtered and concentrated to give aresidue, which was purified by flash chromatography on silica gel togive the product as white solid (20 mg, 41.7% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.26 (s, 1H), 7.69-7.62 (d, 2H), 7.33 (m, 1H), 7.04 (s, 1H),6.85 (s, 1H), 4.40-4.25 (m, 2H), 4.22-4.12 (m, 1H), 3.75-3.62 (m, 1H),3.61-3.52 (m, 1H), 2.62-2.51 (m, 2H), 0.95-0.82 (m, 4H).MS APCI (+) m/z:552.9, [M+H].

Examples 25-33 Preparation of Compounds 25-33

Compounds 2533 were prepared following similar procedures used forcompounds 1-8.

Compound 25

¹H NMR (400 MHz, DMSO) δ 11.74 (s, 1H), 8.96 (s, 1H), 8.04 (s, 1H), 7.91(s, 1H), 7.56 (d, J=9.6 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 6.41 (m, 1H),4.73 (s, 1H), 3.86 (m, 2H), 3.56 (m, 2H). MS APCI (+) m/z: 429.4 [M+H].

Compound 26

¹H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 8.98 (s, 1H), 8.05 (s, 1H), 7.90(s, 1H), 7.55 (d, J=9.6 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 6.41 (m, 1H),4.71 (s, 1H), 3.82 (m, 2H), 3.55 (m, 2H). MS APCI (+) m/z: 418.4 [M+H].

Compound 27

¹H NMR (400 MHz, DMSO) δ 11.74 (s, 1H), 8.95 (s, 1H), 8.00 (s, 1H), 7.86(s, 1H), 7.54 (d, J=9.8 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.38 (m, 1H),4.69 (s, 1H), 3.82 (m, 2H), 3.57 (m, 2H), 2.55 (s, 3H). MS APCI (+) m/z:396.5 [M+H].

Compound 28

¹H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 8.97 (s, 1H), 8.03 (s, 1H), 7.90(s, 1H), 7.55 (d, J=9.8 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.40 (m, 1H),4.72 (s, 1H), 3.85 (m, 2H), 3.57 (m, 2H). MS APCI (+) m/z: 434.4 [M+H].

Compound 29

¹H NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 8.95 (s, 1H), 8.04 (s, 1H), 7.92(s, 1H), 7.56 (d, J=9.6 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 6.42 (m, 1H),4.75 (s, 2H), 3.68 (m, 4H), 3.38 (m, 1H). MS APCI (+) m/z: 506.3 [M+H].

Compound 30

¹H NMR (400 MHz, DMSO) δ 11.74 (s, 1H), 8.96 (s, 1H), 8.07 (s, 1H), 7.91(s, 1H), 7.58 (d, J=9.4 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.45 (m, 1H),4.76 (s, 2H), 3.70 (m, 4H), 3.40 (m, 1H). MS APCI (+) m/z: 459.4 [M+H].

Compound 31

¹H NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 8.95 (s, 1H), 8.04 (s, 1H), 7.92(s, 1H), 7.58 (d, J=9.6 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.43 (m, 1H),4.73 (s, 2H), 3.71 (m, 4H), 3.39 (m, 1H). MS APCI (+) m/z: 475.8 [M+H].

Compound 32

¹H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 8.93 (s, 1H), 8.01 (s, 1H), 7.90(s, 1H), 7.55 (d, J=9.4 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.41 (m, 1H),3.73 (m, 2H), 0.51 (m, 1H), 0.25 (m, 4H). MS APCI (+) m/z: 486.2 [M+H].

Compound 33

¹H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 8.92 (s, 1H), 8.02 (s, 1H), 7.93(s, 1H), 7.57 (d, J=9.8 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 6.43 (m, 1H),3.75 (m, 2H), 0.52 (m, 1H), 0.26 (m, 4H). MS APCI (+) m/z: 455.8 [M+H].

Examples 34-42 Preparation of Compounds 43-51

Compounds 34-42 were prepared following similar procedures used forcompounds 9-16.

Compound 34

¹H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 9.54 (s, 1H), 8.20 (s, 1H), 8.11(s, 1H), 7.56 (d, 1H), 7.31 (d, 1H), 6.47 (m, 1H), 4.73 (s, 1H), 3.85(m, 2H), 3.55 (m, 2H). MS APCI (+) m/z: 445.3 [M+H].

Compound 35

¹H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 9.53 (s, 1H), 8.24 (s, 1H), 8.14(s, 1H), 7.56 (d, 1H), 7.33 (d, 1H), 6.50 (m, 1H), 4.74 (s, 1H), 3.85(m, 2H), 3.55 (m, 2H). MS APCI (+) m/z: 434.4 [M+H].

Compound 36

¹H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 9.54 (s, 1H), 8.22 (s, 1H), 8.12(s, 1H), 7.54 (d, 1H), 7.30 (d, 1H), 6.45 (m, 1H), 4.73 (s, 1H), 3.84(m, 2H), 3.56 (m, 2H), 2.51 (s, 3H). MS APCI (+) m/z: 412.5 [M+H].

Compound 37

¹H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 9.55 (s, 1H), 8.23 (s, 1H), 8.11(s, 1H), 7.52 (d, 1H), 7.28 (d, 1H), 6.43 (m, 1H), 4.75 (s, 1H), 3.83(m, 2H), 3.55 (m, 2H). MS APCI (+) m/z: 450.5 [M+H].

Compound 38

¹H NMR (400 MHz, DMSO) δ 11.78 (s, 1H), 9.54 (s, 1H), 8.20 (s, 1H), 8.11(s, 1H), 7.56 (d, 1H), 7.32 (d, 1H), 6.49 (m, 1H), 4.75 (s, 2H), 3.67(m, 4H), 3.36 (m, 1H). MS APCI (+) m/z: 522.3 [M+H].

Compound 39

¹H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 9.55 (s, 1H), 8.21 (s, 1H), 8.12(s, 1H), 7.57 (d, 1H), 7.31 (d, 1H), 6.50 (m, 1H), 4.74 (s, 2H), 3.68(m, 4H), 3.35 (m, 1H). MS APCI (+) m/z: 475.3 [M+H].

Compound 40

¹H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 9.53 (s, 1H), 8.22 (s, 1H), 8.13(s, 1H), 7.58 (d, 1H), 7.32 (d, 1H), 6.51 (m, 1H), 4.75 (s, 2H), 3.70(m, 4H), 3.36 (m, 1H). MS APCI (+) m/z: 491.7 [M+H].

Compound 41

¹H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 9.55 (s, 1H), 8.25 (s, 1H), 8.14(s, 1H), 7.60 (d, 1H), 7.31 (d, 1H), 6.52 (m, 1H), 3.72 (m, 2H), 0.50(m, 1H), 0.25 (m, 4H). MS APCI (+) m/z: 471.7 [M+H].

Compound 42

¹H NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 9.54 (s, 1H), 8.23 (s, 1H), 8.14(s, 1H), 7.62 (d, 1H), 7.33 (d, 1H), 6.50 (m, 1H), 3.71 (m, 2H), 0.49(m, 1H), 0.23 (m, 4H). MS APCI (+) m/z: 502.3 [M+H].

Examples 43-51 Preparation of Compounds 43-51

Compounds 43-51 were prepared following similar procedures used forcompounds 17-24.

Compound 43

¹H NMR (400 MHz, DMSO) δ 11.92 (s, 1H), 8.68 (s, 1H), 8.55 (s, 1H), 7.35(d, 1H), 7.23 (d, 1H), 6.37 (m, 1H), 4.72 (s, 1H), 4.04 (m, 2H), 3.78(m, 2H). MS APCI (+) m/z: 446.3 [M+H].

Compound 44

¹H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 7.38(d, 1H), 7.24 (d, 1H), 6.41 (m, 1H), 4.70 (s, 1H), 4.04 (m, 2H), 3.79(m, 2H). MS APCI (+) m/z: 435.4 [M+H].

Compound 45

¹H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 7.34(d, 1H), 7.23 (d, 1H), 6.40 (m, 1H), 4.68 (s, 1H), 4.06 (m, 2H), 3.80(m, 2H), 2.52 (s, 3H). MS APCI (+) m/z: 413.5 [M+H].

Compound 46

¹H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 7.33(d, 1H), 7.21 (d, 1H), 6.38 (m, 1H), 4.71 (s, 1H), 4.02 (m, 2H), 3.77(m, 2H). MS APCI (+) m/z: 451.3 [M+H].

Compound 47

¹H NMR (400 MHz, DMSO) δ 11.88 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 7.35(d, 1H), 7.24 (d, 1H), 6.41 (m, 1H), 4.70 (s, 1H), 4.03 (m, 4H), 3.68(m, 1H). MS APCI (+) m/z: 523.3 [M+H].

Compound 48

¹H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 7.33(d, 1H), 7.25 (d, 1H), 6.39 (m, 1H), 4.71 (s, 1H), 4.05 (m, 4H), 3.67(m, 1H). MS APCI (+) m/z: 476.3 [M+H].

Compound 49

¹H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 7.36(d, 1H), 7.23 (d, 1H), 6.40 (m, 1H), 4.72 (s, 1H), 4.05 (m, 4H), 3.69(m, 1H). MS APCI (+) m/z: 492.7 [M+H].

Compound 50

¹H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 7.35(d, 1H), 7.25 (d, 1H), 6.41 (m, 1H), 3.70 (m, 2H), 0.51 (m, 1H), 0.26(m, 4H). MS APCI (+) m/z: 503.4 [M+H].

Compound 51

¹H NMR (400 MHz, DMSO) δ 11.91 (s, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 7.38(d, 1H), 7.25 (d, 1H), 6.42 (m, 1H), 3.72 (m, 2H), 0.52 (m, 1H), 0.25(m, 4H). MS APCI (+) m/z: 472.7 [M+H].

Example B-1 Cell Growth Inhibition Assays Materials

-   CELLS: HT29, COLO205 and A375 cells were obtained from the Cell    Resource Center at the Institute of Basic Medical Research, Chinese    Academy of Medical Sciences.-   REAGENTS: DMEM/F12 (GIBCO), 0.25% trypsin (GIBCO), MTT (5 mg/ml),    DMSO, PBS-   INSTRUMENT: 37° C., 5% CO₂ cell incubator, the TECAN infinite TM200    Series multifunctional microplate reader, clean benches, cell    counting board-   CONSUMABLES: 96-well plates (CORING)

Methods 1 (HT29)

-   1. When the HT29 cells reach their exponential phase of growth,    4×103 cells/well were plated into 96-well plates, the edge of plates    were filled with sterility PBS, at the same time, filled three holds    only with medium as blank group.-   2. The plates were cultured in a humidified 5% CO₂ incubator at    37° C. for 24 h, and allowed to proliferate for reaching their    exponential phase of growth.-   3. Samples were dissolved in DMSO (dimethyl sulfoxide), the    concentration of Samples is 10 mmol/L, 1 mmol/L, 100 μmol/L, 10    μmol/L, 1 μmol/L, 0.1 μmol/L, and further diluted with cell culture    medium. The final does concentration were 10 μmol/L, 1 μmol/L, 100    nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L, 0 nmol/L (the control    group). The final DMSO concentration used was 1‰ of total volume of    medium in all treatments, including the control group.    -   Blank: medium    -   Control: the same dose of DMSO with experiment. Group, the DMSO        was diluted with cell perfect culture medium.    -   Experiment: the cells were treated with the concentration of 10        μmol/L, 1 μmol/L, 100 nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L.-   4. The plates were cultured in a humidified 5% CO₂ incubator at    37° C. for 72 h. 20 μL of    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)    reagent (5 mg/mL) in phosphate buffered serum (PBS) was added to    each well.-   5. The plates were cultured in a humidified 5% CO₂ incubator at    37° C. for 4 h. Subsequently, the solution was aspirated and 150 uL    dimethyl sulfoxide was added to release the formed formazan crystals    from the living cells mitochondria into the solution.-   6. After moderated shaking for 3 min, absorbance was measured at 490    nm using microplate reader.

Methods 2 (A375)

-   1. When the A375 cells reach their exponential phase of growth,    5×103 cells/well were plated into 96-well plates, the edge of plates    were filled with sterility PBS, at the same time, filled three holds    only with medium as blank group.-   2. The plates were cultured in a humidified 5% CO₂ incubator at    37° C. for 24 h. Allowed to proliferate for reaching their    exponential phase of growth.-   3. Samples were dissolved in DMSO (Dimethyl Sulfoxide), the    concentration of Samples is 10 mmol/L, 1 mmol/L, 100 μmol/L, 10    μmol/L, 1 μmol/L, 0.1 μmol/L, and further diluted with cell culture    medium. The final does concentration were 10 μmol/L, 1 μmol/L, 100    nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L, 0 nmol/L (the control    group). The final DMSO concentration used was 1‰ of total volume of    medium in all treatments, including the control group.-   Blank: medium    -   Control: the same dose of DMSO with experiment group, the DMSO        was diluted with cell perfect culture medium    -   Experiment: the cells were treated with the concentration of 10        μmol/L, 1 μmol/L, 100 nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L-   4. The plates were cultured in a humidified 5% CO₂ incubator at    37° C. for 72 h. 20 μL of    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)    reagent (5 mg/mL) in phosphate buffered serum (PBS) was added to    each well.-   5. The plates were cultured in a humidified 5% CO₂ incubator at    37° C. for 4 h. Subsequently, the solution was aspirated and 150 uL    dimethyl sulfoxide was added to release the formed formazan crystals    from the living cells mitochondria into the solution.-   6. After moderated shaking for 3 min, absorbance was measured at 490    nm using microplate reader.

Methods 3 (COLO205)

-   1. When the COLO0205 cells reach their exponential phase of growth,    1×10⁴ cells/well were plated into 96-well plates, the edge of plates    were filled with sterility PBS, at the same time, filled three holds    only with medium as blank group.-   2. The plates were cultured in a humidified 5% CO2 incubator at    37° C. for 24 h. Allowed to proliferate for reaching their    exponential phase of growth.-   3. Samples were dissolved in DMSO (Dimethyl Sulfoxide), the    concentration of Samples is 10 mmol/L, 1 mmol/L, 100 μmol/L, 10    μmol/L, 1 μmol/L, 0.1 μmol/L, and further diluted with cell culture    medium. The final does concentration were 10 μmol/L, 1 μmol/L, 100    nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L, 0 nmol/L (the control    group). The final DMSO concentration used was 1‰ of total volume of    medium in all treatments, including the control group.    -   Blank: medium    -   Control: the same dose of DMSO with experiment group, the DMSO        was diluted with cell perfect culture medium    -   Experiment: the cells were treated with the concentration of 10        μmol/L, 1 μmol/L, 100 nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L-   4. The plates were cultured in a humidified 5% CO₂ incubator at    37° C. for 72 h. 20 μl of    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)    reagent (5 mg/ml) in phosphate buffered serum (PBS) was added to    each well.-   5. The plates were cultured in a humidified 5% CO₂ incubator at    37° C. for 4 h. Subsequently, the solution was aspirated and 150 ul    dimethyl sulfoxide was added to release the formed formazan crystals    from the living cells mitochondria into the solution.-   6. After moderated shaking for 3 min, absorbance was measured at 490    nm using microplate reader.

The cell inhibition 1050 values obtained with the HT29 and A375 cellsare shown in Table 5.

TABLE 5 Compound IC₅₀ (nM) No. HT29 A375 1 2.3 0.85 2 8.1 4.6 3 51.861.3 4 138 97.5 5 81.6 125 6 78.3 103 7 283 239 8 1092 738 9 1.0 0.79 1018.5 11.2 11 51.2 61.4 12 738 174 13 98.3 207 14 201 119 15 184 99.8 161306 151 17 1.0 0.24 18 66.4 16.8 19 65.7 49.4 20 687 97.3 21 1078 177022 2620 1160 23 3640 562 24 4370 992

Example B-2 In Vivo Anti-Tumor Efficacy in HT29 Tumor Xenograft Model

Female BALB/c nude mice of 5-6 week old were used for all the in vivoefficacy studies. Mice were injected with HT29 human colon cancer cellsat 5×10⁶ cells per 100 μL SFM into right flank. Tumor volumes weremonitored by caliper measurement using the formula: tumor volume(mm³)=(w²×l)/2, where w=width and c=length in mm of the tumor. When thetumor volumes reached 150˜300 mm³, mice were randomized to treatmentgroups (5˜10 mice per group) to receive compounds (20 mg/kg doses) orvehicle by oral gavage once daily for 16 days. The tumor volumes andbody weight were measured every 2-3 days for data analysis. Tumor growthinhibition (TGI) and body weight changes were calculated compared to thevehicle treated groups. TGI represents the percent volume differentialbetween the treated and control tumors at the time vehicle tumorsexceeded a volume of 1,000 based on formula TGI(%)=(1−(T−To)/(C−Co))*100%.

The results for Compounds 1, 3, 9, 11, 17 and 19 are shown in FIG. 1.The results show that the human colon HT-29 xenograft was highlysensitive to Compounds 9 and 17, which demonstrated 95.1% TGI forCompound 9 at 20 mg/kg and 88.75% TGI for 17 at 20 mg/kg respectivelyafter 16 days of treatment. Compounds 1, 11 and 19 also showedsignificant inhibition of HT29 xenograft growth in nude mice at 20 mg/kgwith TGI at 55.1%, 68.51% and 50.9% respectively. Compound 3 at 20 mg/kgshowed no significant effects on HT29 cancer cell growth with TGI at32.3% in nude mice after 16 days treatment. Reference compound AZD6244showed inhibition of HT29 xenograft growth in nude mice at 20 mg/kg withTGI at 48.3% after 16 days treatment.

Example B-3 In Vivo Anti-Tumor Efficacy in COLO205 Tumor Xenograft Model

The animal use and care protocol was approved by Sundia InstitutionalAnimal Care and Use Committee. Male athymic nude mice (nu/nu; 6 weeks ofage) were obtained from Beijing HFK Bioscience CO., LTD. All animalswere fed with commercial diet and water ad libitum for 1 week before thestudy.

Each mouse was inoculated s.c. in the flank with COLO 205 tumor fragment(˜1 mm³). When rumors reached the appropriate size for staging (170 mm³or as indicated in data graphs), mice were randomized to eight groups(n=6) that received the following treatments: (a) 20% SBE-β-CD in puritywater vehicle, (b) AZD6244 at 10 mg/kg QD, (c) test compound 19 at 10mg/kg QD, (d) test compound 1 at 10 mg/kg QD, (e) test compound 3 at 20mg/kg QD, (f) test compound 9 at 5 mg/kg QD, (g) test compound 11 at 10mg/kg QD, (h) test compound 17 at 5 mg/kg QD. Mice received treatmentsby gavage (10 mL/kg body weight) for the duration of the study. Tumorswere measured twice a week using calipers and their volumes calculatedusing the formula (width²×length)/2. In this experiment, tumors werestaged on day 0, the day of first treatment. The Reference Compounds andthe test compounds were formulated in 20% SBE-β-CD.

The tumor growth inhibition ratio was calculated using the formula:TGI=100×[(tumor volume_(final) for the vehicle-treated group−tumorvolume_(final) for the compound-treated group)/tumor volume_(final) forthe vehicle-treated group]. Tumor growth data are expressed as meantumor volumes±S.E. Differences were considered significant at P<0.05 andstatistical analysis was done using Microsoft Excel.

After 18 days consecutive treatments (QD×18 days), the Referencecompound 1 inhibited 72.80% (P<0.01) of tumor growth, compared with thevehicle control group. The test compound 1, 3, 9, 11, 17 and 19inhibited 91.22% (P<0.01), 47.11% (P<0.05), 94.70% (P<0.01), 82.14%(P<0.01), 95.35% (P<0.01) and 86.22% (P<0.01) of tumor growth,respectively, compared with the vehicle control group.

The results for Compounds 1, 3, 9, 11, 17 and 19 are shown in FIG. 2.

Example B-4 Inhibition of Interleukin-4 (IL-4)

Method:

-   1. Take spleens of BALB/c gene reported mice, culture in RPMI1640    medium (HyClone).-   2. Spleen will be ground into single cell suspension, add red blood    cell lysis buffer (sigma) to suspension, for cracking the red blood    cells.-   3. The cell suspension was filtered, and suspended in 1640 medium    containing 10% serum.-   4. Dissolved compounds with DMSO and diluted with RPMI1640 medium    containing 10% serum, diluted to a final concentration of 200 nM.-   5. According with the concentration of 4×106/mL, 100 μL/well,    calculate the required total number of cells, suspended in the RPMI    1640 medium containing 10% serum. in the cell suspension, added ConA    (Concanavalin A, sigma) (final concentration for 2.5 ng/mL), IL-2    (interleukin-2, R & D) (final concentration of 2 ng/mL), IL-4    (interleukin-4, PeproTech) (final concentration of 20 ng/mL) into    the cell suspension. After mixing, cells were added to 96 well    plates, every hole is 100 μL. Joined the compound solution, 100    μL/well, the cell final concentration is 2×106/mL, the compounds    final concentration is 100 nM. Each compound and control is    three-hole wells, cultured at 37° C. for 48 h.-   6. After 48 h, the plates removed from the incubator and each well    was collected in the flow tube (BD).-   7. Added cells to ice pre-cooling of PBS (phosphate buffer solution)    solution to wash, and in 100 μL of PBS, join the fluorescent    antibody CD4 0.5 μL, put in ice 15 min avoid light.-   8. After dyeing wash antibodies with the ice pre-cooling PBS    solution. And prepare for flow cytometric detection.-   9. Using flow cytometry (BD FACS calibur) select the CD4+ cell    populations, and detect GFP+ cells accounted for the percentage of    CD4+ cells, to determine the impact of compounds on IL-4.-   10. The inhibition rate of IL-4(%)=(Control %−compounds %)/control    %×100%.

Control was DMSO and its concentration was same as the finalconcentration of test compounds. Compounds 1, 3, 9, 11, 17, 19, 25, 34and 43 showed up to 50% IL-4 inhibition.

Example B-5 Inhibition of TNF-α Expression

Method:

-   1. Take spleens of BALB/c gene reported mice, cultured in RPMI1640    medium (HyClone). Spleen was ground into single cell suspension,    added red blood cell lysis buffer (sigma) to suspension, for    cracking the red blood cells-   2. The cell suspension was filtered, and suspended in 1640 medium    containing 10% serum (HyClone), the cell final concentration was    4×10⁶/mL, added LPS to medium and final concentration was 200 ng/mL.-   3. Dissolved compounds with DMSO and diluted with RPMI1640 medium    containing 10% serum, diluted to a final concentration of 200 nM.-   4. Cells were added to 96 well plates, every hole was 100 μL. Joined    the compound solution, 100 μL/well, the cell final concentration was    2×106/mL, the compounds final concentration was 100 nM. Each    compound and control is three-hole wells.-   5. Cultured at 37° C. for 24 h.-   6. Centrifuged at 1400 rmp, 7 min by Cell plate centrifuge    (Eppendorf 5810R), drew the supernatant and placed in the new    96-well plates, placed at 4° C. to save.-   7. Using ELISA (enzyme-linked immunosorbent assay) technique for the    determination of the amount of TNF-α in the 24 hours.

Control was DMSO and its concentration was same as the finalconcentration of test compounds. Compounds 1, 3, 9, 11, 17, 19, 25, 34and 43 showed up to 40% inhibition.

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

1. A compound of the formula (I):

or a salt, prodrug or solvate thereof, wherein: X¹ is CR¹¹ or N; X² isO, S or carbonyl; R¹, R², R⁴ and R⁵ are independently hydrogen, halo,nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy,acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino,carboxy, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀cycloalkyl; R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, mercapto, C₁-C₁₀alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a),—SO₂N(R^(c))R^(d), —N(R^(c))R^(d), —C(O)OR^(b), C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl; R^(a) is C₁-C₁₀ alkyl orC₆-C₁₄ aryl; each R^(b), R^(c) and R^(d) is independently hydrogen orC₁-C₁₀ alkyl; R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)R⁹ or—NHSO₂R¹⁰; each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylC₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; R⁹ is C₁-C₁₀ alkyl,C₃-C₁₀ cycloalkyl or C₆-C₁₄ aryl; R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl orC₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; and R¹¹ is hydrogen, C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkylC₁-C₁₀ alkyl; wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynylor C₃-C₁₀ cycloalkyl moiety may be unsubstituted or substituted with oneor more groups independently selected from the group consisting ofhydroxy, oxo, halo, cyano, nitro, trifluoromethyl, azido, amino, carboxyand mercapto; provided that if X¹ is CH, X² is O or S, R¹ is methyl orchloro, R² is hydrogen and R³ is iodo, then R⁶ is —NHSO₂R¹⁰ or—C(O)N(R⁸)OR⁷ where R⁷ is C₁-C₁₀ alkyl substituted with at least onehydroxy group. 2-5. (canceled)
 6. The compound of claim 1, or a saltthereof, wherein X² is O or S. 7-8. (canceled)
 9. The compound claim 1,or a salt thereof, wherein R¹ is halo. 10-15. (canceled)
 16. Thecompound claim 1, or a salt thereof, wherein R² is hydrogen. 17-19.(canceled)
 20. The compound of claim 1, or a salt thereof, wherein R³ isiodo or bromo. 21-37. (canceled)
 38. The compound of claim 1, or a saltthereof, wherein R⁴ is hydrogen. 39-43. (canceled)
 44. The compound ofclaim 1, or a salt thereof, wherein R⁵ is fluoro. 45-48. (canceled) 49.The compound of claim 1, or a salt thereof, wherein R⁶ is —C(O)N(R⁸)OR⁷.50-52. (canceled)
 53. The compound of claim 49, or a salt thereof,wherein R⁷ is C₁-C₁₀ alkyl substituted with at least one hydroxy group.54-59. (canceled)
 60. The compound of claim 49, or a salt thereof,wherein R⁸ is hydrogen. 61-73. (canceled)
 74. The compound of claim 1,or a salt thereof, wherein the compound is selected from the groupconsisting of:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide;N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide;5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide;5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide;N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropanesulfonamide;N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide;N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazol-6-yl)cyclopropanesulfonamide;N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide;4-fluoro-5-((2-fluoro-4-bromophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide;4-fluoro-5-((2-fluoro-4-trifluoromethylphenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide;4-fluoro-5-((2-fluoro-4-methylthiophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide;5-((4-trifluoromethoxy-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide;5-((2-fluoro-4-iodophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide;5-((4-bromo-2-fluorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide;5-((4-bromo-2-chlorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide;4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-cyclopropylmethyl-benzo[d]oxazole-6-carboxamide;4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-cyclopropylmethyl-benzo[d]oxazole-6-carboxamide;4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide;N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide;5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide;5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d]thiazole-6-carboxamide;N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropanesulfonamide;1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide;N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)cyclopropanesulfonamide;N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide;4-fluoro-5-((2-fluoro-4-bromophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazol-6-carboxamide;4-fluoro-5-((2-fluoro-4-trifluoromethylphenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazol-6-carboxamide;4-fluoro-5-((2-fluoro-4-methylthiophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazol-6-carboxamide;5-((4-trifluoromethoxy-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]thiazol-6-carboxamide;5-((2-fluoro-4-iodophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]thiazol-6-carboxamide;5-((4-bromo-2-fluorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]thiazol-6-carboxamide;5-((4-bromo-2-chlorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]thiazol-6-carboxamide;4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-cyclopropylmethyl-benzo[d]thiazol-6-carboxamide;4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-cyclopropylmethyl-benzo[d]thiazol-6-carboxamide;4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide;N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide;5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide;5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d][1,2,3]thiadiazole-6-carboxamide;N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide;1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide;N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide;N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d][1,2,3]thiadiazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide;5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide;4-fluoro-5-((2-fluoro-4-trifluoromethylphenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6-carboxamide;4-fluoro-5-((2-fluoro-4-methylthiophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6-carboxamide;5-((4-trifluoromethoxy-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6-carboxamide;5-((2-fluoro-4-iodophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide;5-((4-bromo-2-fluorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide;5-((4-bromo-2-chlorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide;4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-cyclopropylmethyl-benzo[d][1,2,3]thiadiazol-6-carboxamide;and4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-cyclopropylmethyl-benzo[d][1,2,3]thiadiazol-6-carboxamide.75-76. (canceled)
 77. The compound of claim 1, or a salt thereof,wherein the compound is selected from the group consisting of:4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide;4-fluoro-5-((2-fluoro-4-bromophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide;5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide;4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide;4-fluoro-5-((2-fluoro-4-bromophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazol-6-carboxamide;5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide;4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide;5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide;and5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide.78. (canceled)
 79. The compound of claim 1, wherein the compound is ofthe formula (J):

or a salt thereof, wherein X¹, X², R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are asdefined in claim
 1. 80. The compound of claim 79, wherein the compoundis of the formula (J-1):

or a salt thereof, wherein R¹, R³, R⁵ and R⁷ are as defined in claim 1.81. The compound of claim 80, or a salt thereof, wherein: R¹ is halo orunsubstituted or substituted C₁-C₁₀ alkyl; R³ is halo, unsubstituted orsubstituted C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy,C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a),—SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b); R⁵ is hydrogen, haloor unsubstituted or substituted C₁-C₁₀ alkyl; and R⁷ is hydrogen,unsubstituted or substituted C₁-C₁₀ alkyl or unsubstituted orsubstituted C₃-C₁₀ cycloalkyl. 82-100. (canceled)
 101. The compound ofclaim 79, wherein the compound is of the formula (J-2) or (J-3):

or a salt thereof, wherein R¹, R³, R⁵, R⁷ and R¹¹ are as defined inclaim
 1. 102. (canceled)
 103. The compound of claim 101, or a saltthereof, wherein: R¹ is halo or unsubstituted or substituted C₁-C₁₀alkyl; R³ is halo, unsubstituted or substituted C₁-C₁₀ alkyl, C₁-C₁₀alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio,halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d),—N(R^(c))R^(d) or —C(O)OR^(b); R⁵ is hydrogen, halo or unsubstituted orsubstituted C₁-C₁₀ alkyl; R⁷ is C₁-C₁₀ alkyl substituted with at leastone hydroxy group; and R¹¹ is hydrogen. 104-115. (canceled)
 116. Thecompound of claim 101, or a salt thereof, wherein: R¹ is fluoro orchloro; R³ is iodo or bromo; R⁵ is fluoro; and R⁷ is selected from thegroup consisting of 2-hydroxyethyl, 3-hydroxy-2-methylpropyl,2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl.
 117. The compound ofclaim 79, wherein the compound is of the formula (J-4):

or a salt thereof, wherein X¹, X², R¹ and R³ are as defined in claim 1.118-136. (canceled)
 137. A pharmaceutical composition comprising acompound of claim 1, or a salt, prodrug or solvate thereof, and apharmaceutically acceptable carrier.
 138. A method of treating a diseaseor condition mediated by MEK comprising administering to an individualin need thereof a therapeutically effective amount of a compound ofclaim 1, or a pharmaceutically acceptable salt, prodrug or solvatethereof.
 139. The method of claim 138, wherein the disease or conditionis rheumatoid arthritis, inflammatory bowel disease or cancer selectedfrom colon cancer, colorectal cancer, lung cancer, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer and skin cancer. 140-144.(canceled)
 145. A kit comprising a compound of claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof.
 146. Amethod of making a compound of the formula (J), or a salt thereof,comprising coupling of a compound of the formula (G), or a salt thereof,with a hydroxylamine derivative of the formula R⁷O—N(R⁸)H or a saltthereof:

wherein X¹, X², R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined in claim 1,and R¹⁴ is hydrogen, benzyl, benzyl substituted with 1 to 3 methoxygroups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ areindependently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.
 147. Themethod of claim 146, wherein: (i) X¹ is N and X² is S:

further comprising converting a compound of the formula (F-1a) or a saltthereof to the compound of the formula (G-1a) or a salt thereof:

wherein R¹⁵ is allyl, benzyl, benzyl substituted with 1 to 3 methoxygroups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ areindependently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl; (ii) X¹ isCR¹¹ and X² is O:

wherein R¹¹ is as defined in claim 1, further comprising converting acompound of the formula (F-2a) or a salt thereof to the compound of theformula (G-2a) or a salt thereof:

or (iii) X¹ is CR¹¹ and X² is S:

where R¹¹ is as defined in claim 1, further comprising converting acompound of the formula (F-3a) or a salt thereof to the compound of theformula (G-3a) or a salt thereof:

148-165. (canceled)